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Full text of "Opening Statements Before the Committee on Appropriations"




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OPENING STATEMENTS 
for the 
National Institutes of Health 



In Connection with 
Appropriation Requests for Fiscal Year 1959 



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National Institutes of Health 
Public Health Service 
U. S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE 



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076929 

SUMMARY OF OPENING STATEMENT 

by 

Director, National Institutes of Health 
Public Health Service 
COMMITTEE ON APPROPRIATIONS 
1959 ESTIMATE 

The nine appropriation requests for the National Institutes 
of Health for 1959 total $2^+1 million, the same as that for the 
preceding fiscal year. Minor program changes include: (l) An in- 
crease in the indirect cost factor for grants, (2) establishment 
within the Division of Research Grants of a graduate training 
program for research in the basic sciences, (3) modest increases 
in support of research fellowships and in training and research 
aspects of physical biology, and {k) lapse of a special appropri- 
ation of $500,000 under the Mental Health Study Act. 

National Support of Medical Research . The support of 
research and research training, both through private sources and 
through public funds from State and Federal appropriations, has 
grown from $88 million a year in 19^7 to $360 million this year. 
The research component of the NIH appropriations represents about 
$150 million, or three-fourths of the Federal government's share, 
and just about kO percent of the Nation's total effort. These 
facts make it imperative that the policies and procedures govern- 
ing Federal support programs be characterized by primary dedication 
to the strength and freedom of the individual scientists and their 
institutions. NIH programs have had the flexibility to meet new 



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- 2 - 
needs, including giving leadership in certain areas of deficiency 
without stifling independent inquiry, the fundamental strength of 
American science. 

Accompli shments . The rapid growth and development of re- 
search in the life sciences in the past ten years has "been 
accompanied by unprecedented accomplishments. Some examples 
might include the discovery of cortisone and other steroids, new 
vaccines, better public health measures to reduce tooth decay, 
new drugs for management of high blood pressure, and development 
and application of a new cancer detection test for women. Pro- 
gress of this kind provides vivid evidence that given adequate 
support, research will continue to progress in the prevention, 
treatment, and control of disease. 

Extramural Activities. The comparatively rapid growth of 
NIH grants and training programs has led to a point at which the 
simple extension of existing programs may be less desirable than 
program changes seeking to reduce fragmentation at the university 
levels. Although NIH programs are focused on research and re- 
search training, it has a responsibility to design the terms and 
conditions under which support of these functions is provided so 
that it does not impose a financial drain on the educational 
institutions. At present, by not paying the full indirect cost 
of research projects supported by grants, we force universities 
to divert their general funds to help finance this research. 



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- 3 - 

Intramural Activities. In our own research at Bethesda, 
there are two needs which warrant special mention. One of these 
relates to the level of remuneration for scientists and scientific 
administrators. It is increasingly evident that if we are to con- 
tinue to attract and retain outstanding scientific personnel, 
further attention must be given to providing career opportunities 
that are parallel to those in medical schools and universities. 
Second, although we are moving ahead with two major construction 
projects (Biologies Standards and a new surgical wing for the 
Clinical Center), the other two authorized projects (Dental 
Research Building and Office Building) should proceed as soon as 
possible within the over-all fiscal policies of the Federal gov- 
ernment as determined by the national economy. 



OPENING STATEMENT 

by 

Director, National Institutes of Health 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"General Research and Services, National Institutes of Health" 

Mr. Chairman and Members of the Committee: 

I am happy to have the opportunity to appear before this Com- 
mittee on behalf of the several Public Health Service appropriation 
requests which in total constitute the 1959 program proposals for the 
National Institutes of Health. 

As in former years, this portion of the Public Health Service's 
presentation is in two parts. The first part relates certain factors 
which pertain to the Institutes as a whole, with emphasis on the part 
we play in the nation's total research effort in the medical and bio- 
logical sciences. The second part has to do with two specific ap- 
propriations administered by the National Institutes of Health as a 
whole rather than by the separate Institutes. One of these is 
entitled "General Research and Services, NIH." The other is the Health 
Research Facilities Construction Program. The other appropriations, 
each representing an Institute, will be presented by the Institute 
Directors. 



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NI H PRCC-RAM SUMMARY - F.Y. 19 59 

First I shall sum up the appropriations requests that are before 
you for the National Institutes of Health. These total $2^+1 million, 
the same amount as appropriated for fiscal year 1958* 

Four points should be borne in mind when looking at the 1959 
summary tables and comparing them with 1958: 

1. As already pointed out to the Committee, a larger portion 
of the research grants item is proposed to support the indirect costs 
of research to the medical schools and universities. 

2. The budget for the first time reflects the establishment, 
by lateral transfer of funds, of a centralized graduate training 
program in the sciences basic to medicine. 

3. Provision has been made through a rearrangement of funds 
for the Senior Research Fellowship program to go forward as planned 
and for modest program increases in both training and research aspects 
of physical biology. 

k, 1958 is the last year authorized for special appropriation 
of $500,000 under the Mental Health Study Act, so that item is not 
contained within the National Institute of Mental Health's 1959 
proposal. 

Otherwise the program presented is essentially the same as that 
for 1958. 

This program is now supporting some 67OO research projects, at 
more than 500 research centers across the country, in the amount of 



- 3 - 
$97«7 million. In addition, support for the training of thousands of 
scientists and medical specialists is provided in the amount of $39*^ 
million. This is done both directly through fellowships and trainee- 
ships and indirectly through training grants to research and teaching 
institutions. The appropriations provide $30 million for assistance 
in the form of matching grants for the construction and equipping of 
research facilities --a program which, incidentally, has seen the 
$60 million in Federal funds during 1957 and 1958 "matched" by $320 
million from private sources, even though only $60 million in matching 
funds was legally required. These programs also provide nearly $12 
million for research contracts in cancer chemotherapy, $5*5 million 
for professional and technical assistance, and $10.3 million for 
certain field investigations and control programs. Finally, nearly 
$39 million is provided for the research carried out as a direct 
operation of the Institutes at Bethesda and to a limited degree in 
the field. 

This functional summary of the programs financed by the nine 
NIH appropriations must be viewed in context if it is to be meaningful. 

EVOLUTION OF SUPPORT PROGRAMS 
1957 saw the completion of ten years of marked expansion in 
our nation's medical research effort. At the close of World War II, 
the United States was spending about $88 million a year in a program 
that bore the marks of the war in which it, too, had served so well. 



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Two factors — public support and research opportunity — were at the 
base of the changes that ensued. The dollars available for support 
of research and research training began to increase steadily, with 
part of the increase coming from private sources and part from public 
funds made available through State and Federal appropriations. By 
1950, medical research support was at a level of $l'+0 million. By 
195I+, it was $220 million. Today, it is estimated that nearly $360 
million is being spent for research in medicine and biology in this 
country. Of this, the Federal government provides over half, or $200 
million. The research component of the NIH appropriations represents 
about $150 million, or three-fourths of the Federal government's 
share, and just about 1+0 percent of the nation's total effort. 

PROGRESS: GROWTH, ACCOMPLISHMENTS, AND SPECULATION 
It is evident from the figures just cited that the past ten 

years have seen rapid growth and expansion in the life sciences. 

They have also seen unparalleled advances in the contributions of 

science to life. 

During these years we have seen, for example: 

Cortisone and other steroids for the treatment of rheumatic 

disease. 

..... Vaccines for the prevention of polio, influenza, upper 
respiratory infections. 

..... Radioisotopes join surgery and other radiation sources 
as a means of treating cancer, and the development of a number 
of compounds which ameliorate certain forms of cancer. 



- 5 - 

Development and widespread use of an inexpensive public 

health measure that can cut tooth decay in half. 

Discovery of a wide array of chemical weapons useful in 

the management of high blood pressure. 

A number of findings which have reduced the death rate 

among mothers and infants and also reduced certain of the 
diseases arising from complications during pregnancy and at 
birth. 

Dramatic improvement, through techniques and instrumentation, 

in surgery for congenital heart malformations and hearts damaged 
by rheumatic fever. 

Development and application of a test for early diagnosis 

of a form of cancer in women, permitting treatment before it 
is too late. 

..... Discovery of a family of drugs permitting startling 
advances in the management of mental illness. 

Progress of this kind provides vivid evidence, if such is 
needed, that the planned use of a segment of our national resources 
for medical and biological research is a sound investment, with 
dividends that are both humanitarian and economic. 

I might comment here that although one may perceive progress 
in terms of the better ability to prevent, treat, or cure disease, 
the research upon which such progress is predicated cannot be neatly 
categorized. It is just as well, perhaps, for research programs to 
be set up so that their very names (heart, cancer, mental health) 
serve as a constant reminder that the ultimate end of research is 
useful knowledge. Having served that purpose, however, it is essential 
that such programs then maintain a research framework within which 
there is optimal opportunity for representation from and interplay 



- 6 - 
among the full range of scientific disciplines and medical specialties. 
For increasingly it becomes evident that as research probes deeper 
and deeper into the areas of darkness that can be illuminated only 
by the intellect and the curiosity and the perseverance of man, the 
separation of science into components such as basic vs applied, lab- 
oratory vs clinical, or even physical vs biological, becomes a 
virtually meaningless exercise in semantics. Science is one in its 
essential aspects, and of paramount importance is the provision of 
means for each scientist, regardless of his discipline, to contribute 
freely to the resolution of the problems under attack. 

Those of us who administer the research programs derived from 
the legislative and fiscal actions of Congress count among our greater 
blessings your recognition of several cardinal principles: (l) the 
importance of continuity and stability in the support of research; 
(2) the need to support medical research at the fundamental as well 
as the applied level if sound progress is to be made against the 
major diseases which plague us; and (3) the awareness that science 
cannot guarantee results according to a fixed timetable regardless 
of the level of support. 

Yet, without attempting to prophesy, it seems quite clear that 
the stream of discovery will continue to flow in the years ahead .... 
that the continuing investment in medical research will continue to 
extend life and, perhaps more importantly, extend useful and happy 
living. 



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In this connection, I should like to call to your attention 
an analysis prepared by the Office of the Actuary of the Social 
Security Administration. Actuarial analyses, for me, are generally 
not stimulating reading; but some of the assumptions for this study, 
which is one of the primary bases for forecasting the long-range 
development of the Old Age and Survivors' Insurance program, are 
startling. By the year 2000, it assumes that the average expectancy 
of life after age 60 will increase from the current 17.5 years to 
22 years. The death rate from heart diseases for men 50 years of 
age will be 50 percent of the current rate. The death rate from 
cancer for women 60 years of age will also be only half the current 
rate. Deaths from tuberculosis will be negligible. The year 2000 is 
actually not very remote. Let me remind you that children born this 
year will be only k2 years old in the year 2000. 

These are actuarial projections. There is no one of us in 
biological science who would have the temerity to forecast medical 
progress with such precision. Yet there is no one of us who is not 
confident that such advances will be achieved in the future as in the 
past. It is axiomatic, although certainly not automatic, that results 
of far-reaching consequence will accrue when a concerted effort is 
made to support the most brilliant scientific intellects in a popu- 
lation of 175 million people. 



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- 8 - 
THE NATIONAL PROGRAM 

In our society, the responsibility for providing the support 
for sustained national medical research effort is a shared responsi- 
bility. The fact that the Federal share is roughly 50 percent of 
the total support makes it all the more imperative that the policies 
and procedures governing Federal support programs be characterized by 
a primary dedication to the strength and freedom of the individual 
scientist and his institution. We have tried to help NIH grow in 
such a pattern. 

We have found, for example, that our programs must remain 
flexible if they are to meet the changing and emerging needs of the 
scientific community. We have found that it is possible for us to 
give leadership through stimulation of research in certain areas of 
deficiency without doing damage to the kind of independent inquiry 
which is the fundamental strength of American science. We have 
found, as we look back over the last ten years, that our training 
programs have been in fact a fertile spawning ground for research 
workers, teachers, and specialists of various kinds. We have seen 
in practice the values to be derived from simultaneous support of 
research projects, training, and research facilities — values which 
take shape in a national research effort that is balanced instead of 
disproportionate. And we have seen confirmed time and again the 
wisdom of a grant and award review process through which decisions 
on the individual and the project to be supported are made by a cross- 
section of American science serving as advisors to the Public Health 
Service. 



- 9 - 
I feel, as I reflect on the last decade of development within 
these programs, that they can be a source for pride on the part of 
all those who brought them into being and watched over their needs 
during a period of rapid growth. The Congress has played a genuinely 
objective, bipartisan, far-sighted role in this process. The dis- 
tinguished chairman and the members of this Committee, and your 
colleagues past and present, did not require the overt challenge 
of an earth satellite launched from the other side of the world 
before giving the kind of impetus needed for a national program of 
research in medicine and biology commensurate with the needs and 
aspirations of our people for better health. 

PROGRAM DEVELOPMENTS 

In a presentation of this kind, which must be directed in part 
to a review of this year ' s activities in order to provide a background 
for our 1959 budget proposals, I can but sketch in a few high points. 
The Institute Directors will present the details of their respective 
programs. And we shall be happy to provide such supplemental infor- 
mation as the Committee may wish. 

Research accomplishments can of course be viewed as our primary 
goal. The past year has been productive in this respect. I shall 
not attempt to enumerate or illuminate the findings which have emerged 
through our programs and taken their place in the fabric of today's 
knowledge of health and disease. I should like to bring to your 



- 10 - 

attention, however, the series of documents called "Research High- 
lights of 1957/' prepared to supplement the testimony of our witnesses. 
I am sure you will find these summary statements both interesting 
and informative. 

There have been, in addition, a number of program developments 
which warrant special attention, 

Research contract and patent problems are being solved, 

permitting effective participation by industry in the cancer 
chemotherapy program. 

Other collaborative programs, notably the study of 

tranquillizing drugs and the study of perinatal influences on 
such diseases as cerebral palsy and mental retardation, have 
become solidly established. 

..... The first of a number of broad, university-centered re- 
search programs focused on the multiple health problems of 
our elder citizens has been established at Duke University, 
and at least two other such projects are in negotiation. 

Scientific interest and attention have been brought to 

bear on the hitherto relatively neglected research problems of 
gastroenterology. 

..... Essential first steps have been taken to give new impetus 
to research and training in the field of physical biology, 
including study of the biological effects of ionizing radiation. 

Results are being achieved in a broad public health pro- 
gram seeking reduction in rheumatic heart disease by control 
of streptococcal infections related to rheumatic fever 

. .... Negotiations have been completed leading to establishment 
in Panama of a small field laboratory for study of tropical 
diseases, particularly arthropod-borne viral diseases, repre- 
senting important Pan-American public health, military, and 
economic problems. 

Our research and vaccine development program to combat 

the Asian influenza epidemic was conducted with signal 
effectiveness and dispatch. 



- 11 - 

..... The developmental program focused on how to bring cancer 
of the uterine cervix under control by widespread use of an 
exfoliative cytology test for early diagnosis arrived at a 
point where a portion of the program emphasis could be shifted 
to the Bureau of State Services so as to encourage wide 
application of knowledge already at hand. 

Progress was evident, both in recruitment and in con- 
version of facilities, on the project under which our scientists 
will collaborate with St, Elizabeths in the study of therapy 
of mental illness. 

A central program supporting graduate training in the 

basic sciences was established in the Division of Research 
Grants. 

The research fellowships program was broadened to permit 

a limited number of outstanding young scientists from other 
countries to compete for support while studying in American 
research centers. 

The program for translation and dissemination of the 

Russian literature in medicine and biology progressed satis- 
factorily in its second year amid growing indications of its 
interest and value for scientists in this country. 

For each Institute there was established a board of 

distinguished scientific advisors to review and make recom- 
mendations concerning its direct research operations at 
Bethesda. 

Initial steps were taken toward the strengthening of the 

program analysis and evaluation functions for NIH as a whole, 
with primary initial emphasis on the collection and processing 
of data bearing on research grant and training activities. 

These are just some of the program developments. They may serve 
to indicate the application of what I believe to be a critically im- 
portant aspect of research program administration — the willingness 
to move, to change, to experiment, to maintain a dynamic quality that 
is in character with our society itself. 



- 12 - 

A LOOK AHEAD - EXTRAMURAL 

As indicated earlier, the combined appropriation requests for 
the National Institutes of Health provide essentially for continuation 
in 1959 of program levels established in 1958 • 

Thus, instead of following the customary procedure of summarizing 
the programs described in the budget justifications that are before 
the Committee, I feel it may be more useful to view the decade ahead 
(as I have just reviewed the decade past) and discuss with you certain 
problems and needs that we face. 

First, in connection with our support programs, I am concerned 
that we as a nation do everything we can progressively to strengthen 
our educational processes. As Director of the National Institutes 
of Health, my greatest interest is in research manpower for medicine 
and biology. By statute and by tradition, our training programs 
are focused primarily if not exclusively at the post-graduate and 
graduate levels. But I am of course keenly aware of how dependent 
we are, in this specialized scientific training, upon the total 
educational structure. Strong academic training, including science, 
at all levels has direct and important bearing on the adequacy of 
scientific manpower in the years ahead. As science can become in- 
troduced more broadly into elementary school curricula, as the 
stature of science teachers and the caliber of science teaching 
improves at high school and college levels, as career opportunities 



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improve, as America fosters and develops respect for intellectual 
pursuits, so will there be marked change in both the number and the 
quality of young people seeking to make research in the life sciences 
their life's work. 

Although we have come a long way since 19M5 toward assuring 
the research grantee and his institution that the Congress and the 
Service intend that our programs should have stability and continuity, 
there remains much to be done in this direction. 

Our programs have come into being during the past decade in 
ways that are characteristic of rapid growth. The program elements, 
whether research or training, have been responses to immediate needs 
within the broad context of our statutory authorities. Thus we have 
seen many different kinds of training programs, for example, and even 
different kinds of research grants programs. All this has been 
necessary and good during a period of time in which all of us con- 
cerned with the evolution of a strong national research program in 
medicine and biology have been feeling our way. 

We have now reached a point, however, at which the simple 
extension of existing programs and the addition of still further pro- 
gram fragments is probably not the wisest way to expend public funds 
and may even be damaging to the institutions in which so much of our 
intellectual strength is focused. I feel we must now seek a means 
for returning to the institutions greater control over their own 
destinies. 



- Ik - 

As one observes the effect of all NIH extramural programs 
upon the institutions conducting research - primarily the various 
schools within universities - the relevance and importance of the 
truism that research and education are inseparably related becomes 
clear. For the future, it is quite clear that the research grant 
and training programs of NIH must be modified to make them in total 
a more effective means of supporting the combined teaching and 
research functions of universities. It is equally clear that means 
must be devised for consideration of the goals and needs of individual 
institutions as totalities. The devices through which these objectives 
will be attained are under study. They include such matters as long 
term, stable, broad program and departmental support. 

In the years ahead, therefore, we must program our support 
activities so that fragmentation at the university level is pro- 
gressively reduced. If this should not happen, and fragmentation 
should increase with the progressive expansion of the base of our 
support, the results could well be catastrophic. 

Another need that I perceive in the years ahead is the need to 
find ways to achieve and maintain balance among those programs under 
grant support which are "planned" research programs, as contrasted 
with research undertaken at the initiative of individual investi- 
gators. The ability to plan and to execute vigorously large-scale 
investigative efforts, requiring voluntary adherence by large numbers 
of investigators to centrally planned research designs, is one of 
the major contributions of the postwar Federal medical research effort. 



- 15 - 
On the other hand, however, I believe such collaborative research 
cannot be permitted to take the place of or otherwise obscure the 
essentiality of the individual and his need for an unrestrained 
opportunity. 

Moreover, I feel such collaborative program efforts, while 
often the only way to secure needed information quickly, can easily 
become wasteful of resources, particularly if their premises remain 
essentially untested during periods of rapid growth. We now have 
four major programs that fall into this category. And while I 
would be the last to attempt to define the ultimate dimension to 
which they should aspire in years to come, I do feel that for a 
period of 12-18 months these four programs — cancer chemotherapy, 
drugs against hypertension, studies of the perinatal period, and 
the psychopharmacology of mental illness — should preferably remain 
at their present levels for a time in order to affirm their pro- 
cedures and solidify their relationships before going ahead. 

Still another requirement for the future is the extension 
of our ability to approach medical research within the context of 
science as a whole, with emphasis on fundamental studies and on 
the training of people highly qualified for investigations of the 
broad spectrum of biological, biochemical, and biophysical phenomena 
underlying all biological systems in normal and abnormal states. 

Finally, and most important of all in terms of the long look 
ahead, the growth and maturation of the support programs administered 
by the National Institutes of Health make it mandatory that we con- 
sider carefully the role of medical schools and universities as 



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- 16 - 
incubators for medical and biological research. Starting with 
extensive support of current research through grants, we then added 
a heavy element of manpower training when it became apparent that 
the production of additional competent scientists was clearly a 
matter of high priority. Then there followed a research facilities 
construction program, completing the research-manpower-facilities 
triad. 

This three-fold program presupposes a healthy, vigorous 
university world capable of bearing this added workload. The total 
research effort, which is a big one, can be fully effective only if 
the universities — including medical schools--are able to serve 
both as a home for scientific scholarship of the highest order and 
as centers for education of the highest caliber. Such a sound base, 
unfortunately, does not exist with any degree of uniformity at this 
time. 

I agree with those who say that the attainment of a stronger 

total university structure is a matter of pressing national urgency. 

I should like, if I may, to quote briefly on this subject from a 

report of a discussion of the trustees of the Carnegie Endowment 

for the Advancement of Teaching. The report said: 

"Since the federal government is very much involved in 
American higher education today, it is faced with innumerable 
opportunities either to strengthen or to weaken the fiscal position 
of the colleges and universities, and with innumberable opportunities 
to strengthen or weaken the teaching profession. In everything it 
does, the federal government should exhibit a keen recognition of 
the importance of the teaching profession and it should seek at 
every point to design its own programs in such a way as to achieve 
the strengthening which that profession so badly needs." 



- 17 - 

It Is not our function, as one of the research grant and 
training programs of government, to solve all the financial problems 
of medical schools and universities. On the other hand, we are 
responsible for designing the terms and conditions under which we 
provide aid to research and manpower training so that we do not 
impose a financial drain on the educational institutions. 

At the moment, as the Committee is aware, we do not pay the 
full cost of the research which we support by grants to medical 
schools and universities. The schools divert their general funds 
to help finance research carried out with Public Health Service 
funds, specifically by bearing a portion of the indirect costs or 
overhead on each project. The research must go on, and the schools, 
with a tradition of service to the Nation, cannot and should not 
curtail the research. But to sustain research even at current 
levels, they must weaken themselves. In diverting general funds 
to support research, they reduce their ability to provide attractive 
and stable career opportunities for teachers. They weaken their 
total capacity to teach. And among those they teach are the investi- 
gators of the future! 

This line of reasoning, based essentially upon the impact 
of our present practices on both the teaching function and the 
fiscal strength of medical schools and universities, leads me to 
the conviction that the Public Health Service should pay the full 
indirect costs of the research it supports. 



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A LOOK AHEAD- -INTRAMURAL 

When I look ahead to the next decade in terms of our own 
direct research in laboratories at Bethesda, I find two subjects 
which should be brought to the special attention of the Committee. 

The first of these has to do with our key scientific personnel , 
In the world of science, the professional staff at NIH has a solidly 
established reputation. During a period of rapid growth, we have 
attracted to Bethesda a number of brillant young scientists and a 
few distinguished elder statesmen to complement the effective scien- 
tific corps which derived from the Service's earlier research acti- 
vities. We are proud of our staff. 

Interchange of young scientists at middle grades with medical 
schools and universities is a desirable practice in the aggregate 
and more to be stimulated than avoided. In recent months, however, 
there have been a few more departures from our group than might 
normally be expected. A few of our more senior people have gone 
back to universities or to Industry simply because they were made 
a more attractive offer financially. We, as the Committee knows, 
use both the Commissioned Corps and the Civil Service personnel 
systems. In practice, the two systems have proved compatible. The 
availability first of super grades (GS 16-18) and more recently of 
208(g) positions which can pay up to $19/000 has helped immeasurably 
by freeing up the top and .thus extending the career opportunity for 
the total group. For the years ahead, further attention should be 
given to pay scales, to increasing the number of top positions 



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- 19 - 
available, to strengthening the comparability factors between the 
Commissioned Corps and Civil Service, and by including biologists, 
behavioral scientists, and other categories excluded from certain 
pay benefits in recent Civil Service Commission proposals. Certainly 
a great deal is already being done to make Federal employment more 
attractive for a scientist. My concern is that our salaries be 
competitive with the best universities, since we at Bethesda can ill 
afford to have it otherwise. 

The second point about our intramural program, and again 
looking ahead, relates to completion of the authorized new con- 
struction projects at Bethesda. As the Committee knows, there are 
four such projects. Two of these — new surgical facilities at the 
Clinical Center, and a new laboratory for the regulatory and research 
functions of the Division of Biologies Standards — have funds appropri- 
ated. The Biologies building is now out for bid preparatory to con- 
struction, and while the surgical wing is still in the stage of . 
tentative plans, some progress is being made. 

Of the other two proposed projects which are integral parts 
of the long-range construction program, one is the much-discussed 
laboratory for research activities of the Dental Research Institute, 
and the other is an office building. It is our earnest hope that 
these structures can be built as soon as the national economy permits. 

I will not dwell extensively upon the substance of research . 
in our intramural program, but I cannot leave the discussion of this 
activity without a word or two. The past ten years has seen strik- 
ing growth both in size and complexity of the program of the NIH. 



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The next decade will be primarily one of consolidation. There will 
be areas requiring special consideration, however, and we believe 
modest expansion may be required to provide for special needs and 
opportunities which cannot be made available through reprogramming 
of resources and reorientation of scientific personnel. Physical 
biologjr and germ-free research are two such opportunities which we 
will wish to discuss at length with the Committee in years to come. 
GENERA L RES E ARCH AND SERVICES, NIH 

I should like to turn now very briefly, Mr. Chairman, to the 
appropriation item "General Research and Services, NIH" and to 
certain operations which are carried out at Bethesda under reimburse- 
ments from the several Institutes. 

This appropriation item carries funds for two programs — that 
of the Division of Biologies Standards, and that of the Division of 
Research Grants. 

With the permission of the Committee, background statements 
on the work of these two divisions are being submitted as supplements 
to prepared testimony. The salient points of these statements can 
be quickly summarized. 

The Division of Biologies Standards carries with it an 
appropriation request of $2.1 million, the same as the F.Y. 1958 appro- 
priation. This Division carries out an essential control function of 
the Federal government, assuring the safety and potency of biologies. 
This operation has proceeded smoothly during the past year, 
taking the Asian influenza vaccine problem in stride and continuing 



- 21 - 
to cope with unresolved problems related to polio vaccine. The 
Division has demonstrated competence both in its regulatory function 
and in its research program. A primary need has been quite recently 
satisfied in that we now have permission to proceed to build a 
permanent laboratory facility at Bethesda. As the Committee knows, 
the Division presently is occupying space on loan from a number of 
the Institutes, to the detriment of its own program as well as theirs. 
The new facilities now going into construction will permit the 
Division not only to stay on top of, but ahead of the problems posed 
by such developments in the fields as vaccines for upper respiratory 
illness, mumps, measles, and other new products which will enter the 
biologies control field. 

The Division of Research Grants shows in the materials before 
you as requesting an apparent increase of $3«7 million, from $11.9 
million in 1958 to $15.6 million in 1959* I say apparent because 
the bulk of that increase ($3*2 million) represents funds that were 
transferred from the Institutes during 195$ "to permit central 
administration and development of certain training activities in the 
basic sciences--such as pathology, pharmacology, biochemistry, and 
physiology. The 1959 appropriation request places funds for this 
training activity in the Division of Research Grants base, and 
reduces the training activities of the Institutes by a corresponding 
amount. In addition, this Division continues to sustain through 
research grants a sizeable part of our total investment in those 
fundamental or basic aspects of the biological sciences which are 



- 22 - 

outside of the areas of interest of the several Institutes. It also 
supports a number of established and a few experimental programs in 
the support of research training. 

OTHER CENTRAL ACTIVITIES FINANCED BY REIMBURSEMENT 
Two other divisions — the Division of Business Operations and 
the Division of Research Services — provide, for the sake of economy 
and efficiency, certain supporting services on a centralized basis. 
These services are equivalent to a number of small businesses con- 
ducted by our organization because of their essential integration 
with the substance of research. They are projected at essentially 
the same levels for 1959 as obtains for 1958* Activities in these 
service areas are under continuing scrutiny to devise more efficient 
and effective ways to provide service. Also under serious review 
are ways and means for modification of financing of these services 
under the Management Fund, which was set up last year to provide a 
system for equitable charges for services to the Institute programs. 
Hopefully this study will progress to a point of reporting by the 
time of our hearings next year. 

The last of these central divisions, in organizational 
terms, is the Clinical Center. We are now entering upon the fifth 
year of occupancy of this facility designed to foster the gradual 
development of clinical investigations closely integrated with 
laboratory studies in each of the seven Institutes. Although short- 
age of highly skilled professional and technical workers for patient 
care and diagnostic services is a somewhat lesser problem, we are 
only beginning to understand the difficulty of far advanced planning 



- 23 - 
for these supporting services in the face of rapidly changing research 
needs. Nonetheless, there is ample evidence that this unique facility- 
is effectively serving to advance the research objectives of the 
Institute programs. Full utilization of the Clinical Center resources 
is near at hand. This has been a gradual process. When 195^ is com- 
pared vith 1957> the progress in utilization of the facility becomes 
apparent. Bed days increased from 53,000 to 170,000. Patient 
admissions rose from 1,000 to 2,500. Diagnostic screening and 
research follow. up visits by patients on an outpatient basis increased 
from 3>800 to 21,300. The Congress had a primary role in fostering 
the construction and operation of the Clinical Center as part of our 
research operation at Bethesda. It has good reason to be proud of 
the contributions that have been and are being made because of the 
research opportunities the Clinical Center provides. 

I would like to comment on one further aspect of our central 
operations. 

Until recently, we have carried out a small analytical function 
within the Office of Research Planning. This office has been pro*- 
vided with additional resources in order to extend its analytical 
studies to include more precise analyses of the support of research 
in biology and medicine from diverse sources, both public and private. 
Coupled with this has been an extension of analytical and evaluative 
functions in the Division of Research Grants and within the several 
Institutes. The combined product of these analyses will serve as a 
ready point of reference for program review and program planning. 



- 2k - 
These functions have assumed considerable importance as our pro- 
grams of research grant and training support have developed into 
a position of significance to the entire national research effort. 
The analytical program will be in full swing by the end of the . s <■ 
present fiscal year, being presently (for the most part) in the 
stage of organization and definition of mission. 

SUMMARY 

You have before you, Mr. Chairman and members of the Committee, 
nine appropriation requests totalling $2^1 million. 

Together, they constitute a vitally important segment of the 
total national research effort in the biological sciences. 

I should like to conclude my remarks with a word about the 
place of biology in the totality of science. 

The concept of the biological sciences continues to broaden. 
New knowledge and new techniques permit the investigator to probe 
deeper and deeper into the mysteries of life at the molecular and 
sub-molecular levels. At the other end of the scale, the investi- 
gative team may probe the equally mysterious challenges that are 
inherent in the study of man and his relation to other men and to 
the complex environment in which men dwell. 

As the scope of the biological sciences has broadened, the 
number of scientific disciplines engaged in biological investi- 
gations has increased. Just as the past decade has seen significant 
contributions by the chemist to the life sciences, for example, so 
the years ahead offer dramatic promise of contributions of equal or 



- 25 - 
perhaps even greater significance by the physical scientist and the 
mathematician. This further evidence of the essential unity of 
science comes at a time when science has been accorded new prominence 
on the national and international scene. We are deeply concerned, 
and quite properly so, with such current issues as scientific careers, 
science education, science and international good will, science and 
public policy, the substance of science, and the support of science. 

It is my hope that as this emphasis on science takes shape 
and focus, nothing will be done as an expedient that does damage to 
the sound and very fundamental processes of science today. My parti- 
cular concern is that the unity of science be strengthened that 

there be no wedges driven between science and society, science 
education and total education, between the physical sciences and 
the biological sciences, between basic science and that part of 
science which seeks application in practice. 

It is my belief, and I am confident this is reflected in 
the programs of the Institutes, that science will advance effectively 
only if the unity of science, and the inseparable links between 
education and research are in practice major guides to national 
science policy. 



OPENING STATEMENT 

by 

Director, National Institutes of Health 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for, 

"Grants for Construction of Health Research Facilities 

Public Health Service" 

Mr. Chairman, Members of the Committee: 

Public Health Service grants for construction of health 
research facilities were authorized by the Health Research Facilities 
Act of 1956 (Title VII of the Public Health Service Act, as amended 
by PL 835, 8Uth Cong.). It provided for health research facilities 
construction grants "to non-Federal public and non-profit institutions 
for the constructing and equipping of facilities for research in the 
sciences related to health — medicine, osteopathy, dentistry, and 
fundamental and applied sciences when related thereto." 

The basic legislation authorizes appropriations of $30 
million in each of the three years, 1957> 1958 and 1959. Appropriations 
of the $30 million were made by Congress for both 1957 and 1958. The 
$30 million requested for 1959 would utilize the full authorization 
provided. 

The National Advisory Council on Health Research Facilities, 
required by the legislation, advises the Surgeon General on all policy 



-2- 
matters and on all applications for health research facilities grants. 
This Council consists of the Surgeon General of the Public Health 
Service as Chairman, one ex officio member from the National Science 
Foundation, and twelve appointive members. The Surgeon General may 
make a grant only if the Council has recommended approval and the 
institution has agreed at least to match the funds to be provided by 
the Public Health Service. 

The first annual report was submitted on January 15, 1957> to 
the President, who submitted it to the Congress on February 6, 1957* 
The report was referred to the House Committee on Interstate and 
Foreign Commerce and was printed as House Document No, 21, 85th 
Congress. The second annual report also has been forwarded to the 
President. These two reports provide documentation on (l) the 
general purposes of the program; (2) accomplishments to date, 
including number of applications reviewed, number of applications 
recommended for approval, and amount of funds paid; (3) general 
comments as to impact of the program on the country; and (k) the 
estimate of additional future needs. This opening Statement incor- 
porates seme of the material in these two annual reports and provides 
additional comment. 

PROGRESS REPORT ON GRANTS AWARDED 

Two hundred and forty institutions throughout the country 
have submitted formal applications for health research facilities 
grants and 26 additional institutions have officially indicated their 



-3- 

plans to submit applications prior to June 30; 1958; which is the 
final submission date for such applications (Title VII, Public 
Health Service Act as amended) * More than 1+00 additional sets of 
application forms have been sent to institutions that have expressed 
their interest in this program. Daily evidence of such interest 
continues to be reflected in the many telephone calls and personal 
visits with staff by representatives of such institutions relative 
to submission of applications by June 30. The total need for Federal 
funds for health research facilities of the 266 institutions is $176 
million. The requirements of the additional institutions which have 
requested the 400 sets of application forms cannot be realistically 
estimated at this time. 

In accordance with the recommendations of the National 
Advisory Council on Health Research Facilities, which were made 
following project- site visits and full discussion and evaluation of 
the individual requests, the Surgeon General awarded in Fiscal Year 
1957; 109 grants to 69 institutions totalling $29, 999; 905- From 
Fiscal Year 1958 funds, the Council recommended and the Surgeon 
General approved 1^-2 grants to 108 institutions totalling $30,000,095. 
A recently prepared list of these grants by State and institution 
is being made available to the Committee. Please note that the list 
shows a reduction in the $100 million requested for these particular 
projects to the total of $60 million awarded during 1957 and 195&. 



. k - 

It also shows the support from Fiscal Year 1959 funds recommended 
for approval prior to the January 1958 meeting of the Council. 

In January, the Council reviewed additional projects for 
payment from the $30 million requested for Fiscal Year 1959* The 
final decision as to the full use of Fiscal Year 1959 funds must, 
however, reflect consideration of all applications which will he 
received prior to June 30; 1958* It is expected that this consider- 
ation will be postponed until the Fall Council meeting. 

The Committee will be pleased with the actual progress on 
construction accomplished to date through the award of these funds. 
Of the 109 grants made from Fiscal Year 1957 funds, $6 projects were 
supported and an additional 13 supplemental awards for equipment were 
provided. Of the 96 projects, 9 are completed, 20 are beyond the 
75/o stage of construction, 19 additional ones are beyond the 50$ 
stage, 18 are beyond the 25$ stage, and the remaining 30 are either 
under construction or will be under construction by June 1958. Of 
these 96 projects, 57 represent grants to medical schools, 6 to 
dental schools and one to a school of public health; private 
non-profit health research institutions received 15 grants, public 
research institutions received 2 grants, and 15 were awarded to 
colleges and universities. It i6 too early to report on the construc- 
tion progress of the projects awarded from Fiscal Year 1958 funds 
except to point out that most of them are already either under 
contract or in the advanced planning stages. 



-5- 

IMPACT OF PROGRAM AND FUTURE MEED 
The effect of this program on research planning for the 
future has been most gratifying. Confirming evidence of the reali- 
zation of the importance of this program has been reflected in the 
outstanding contributions of the 12 distinguished individuals from 
all parts of the United States who serve on the National Advisory 
Council on Health Research Facilities. In addition to the exhaustive 
deliberations and discussions in their quarterly meetings, the members 
of this Council have devoted a considerable portion of their time 
during the first 18 months to visits with officials and staff of 
the applicant institutions. Teams of Council members, accompanied 
in each case by a staff assistant, have made more than 350 project- 
site visits. The resultant reports have proved invaluable in the 
Council discussions of the formal requests. The visits have also 
greatly assisted the administrative and teaching staffs of the 
applicant institutions in their understanding of the program in 
relation to local needs. These administrative and teaching staff 
people have been most cooperative and have readily provided information 
needed by the Council for adequate evaluation of the needs of the 
particular institutions in relation to those of the total country. 
As fully anticipated, the awarding of the 251 grants in the 
amount of $60 million to date has markedly stimulated local contrib- 
utions and development of construction plans. Actually, the $60 



- 6 - 
million have been awarded to projects totalling over $390 million in 
construction costs. The availability of the Federal funds has in 
numerous instances been the catalyst needed to stimulate the comple- 
tion of plans for urgently needed facilities. It is known that in 
some cases, the local money had been conditionally promised, contin- 
gent upon the securing of matching Federal or other funds. 

The Council has sought, through the support recommended, to 
"improve and expand the health research facilities of the Nation," 
as specified by the Act. All grants have been recommended in the 
belief that they have reasonable assurance of doing so. In some 
instances, reduced amounts have been recommended in the belief that 
a research program more modest than that desired was all that was 
justified. Hospitals with records of limited research activity some- 
times fell into this category. With the $90 million authorized by 
current legislation, the Council has felt required to use previous 
accomplishments and promise for the future as important criteria; 
and as a result it has recommended greater support to universities 
with graduate schools and professional schools such as medicine, 
dentistry, nursing, pharmacy, public health, veterinary medicine, 
and sanitary engineering. 

Special attention of the Committee is invited to the fact 
that the health research facilities program was not intended to 
provide support of educational facilities. The Council therefore 
most carefully evaluated all proposals in order to eliminate any 



,-((. 



- 7 - 
portions of the requests which represented teaching or educational 
functions. Quite naturally, the Council was influenced by the 
teaching advantages which were afforded by some of the proposed 
research facilities. 

In the 18 months of operation to date, it has teen continuously 
obvious that, as expected by the Congress, this program has stimulated 
local contributions toward the building of health research facilities 
which have been generally recognized as most urgently needed. 



ATTACHMENT A 

DIVISION OF BIOLOGICS STANDARDS 
BACKGROUND 

The Federal Government's responsibility for the control of 
biological products began on July 1, 1902, with the passage by the 
Congress of an Act to regulate the sale in interstate commerce of 
all viruses, serums, toxins, and analogous products applicable to 
the prevention and cure of diseases of man. The statute, now in- 
cluded in the Public Health Service Act, is basically the same as 
in 1902, when the technical responsibilities of the biologies pro- 
gram were assigned to the National Institutes of Health, then known 
as the Hygienic Laboratory. In 1937 > the Laboratory of Biologies 
Control was created within the National Institutes of Health, and 
in 19^8 it was made a part of the National Microbiological Insti- 
tute. In June 1955; authority was granted the Surgeon General by 
the Secretary of the Department of Health, Education, and Welfare 
to expand the biologies control function of the Public Health Serv- 
ice to the status of a separate division within the National Insti- 
tutes of Health, called the Division of Biologies Standards. 

GENERAL MISSION 

The Division of Biologies Standards is responsible for ad- 
ministering the provisions of the Public Health Service Act and 
Regulations pertaining to the production of all biologic products-- 
vaccines, serums, toxins, antitoxins, and analogous products, 



- 2 - 
including human blood and its derivatives—offered for sale, barter, 
or exchange in interstate commerce. 

Close surveillance of production and constant improvement 
in quality of these products is essential, since many of them are 
derived from living organisms such as bacteria and viruses, and 
all, by their nature, are potentially dangerous if improperly pre- 
pared and tested. 

The development of realistic standards for these products 
and the exercise of proper control over them can be effective only 
if backed by an active research program of sufficient flexibility 
to provide information as it is needed for the formulation of such 
standards. One of the specific aims of the Division since its cre- 
ation has been the development of a strong research program based 
on the premise that the control of biological products can only be 
successful when supported by such a program. 

Through the use of biologic products, such infectious dis- 
eases as smallpox, diptheria, typhoid, yellow fever, tetanus, 
rabies and poliomyelitis can now be prevented or treated. Success 
achieved in these and similar areas, however, does not mean that 
vigilance in control can be lessened. 

Much work remains to be done in controlling other Infectious 
and related diseases, such as influenza, measles, mumps, tubercu- 
losis, hepatitis, and various allergies. Experience with polio- 
myelitis vaccine during the past few years and the renewed interest 



- 3 - 
in influenza vaccine during the past year indicates that the develop- 
ment of new biological products or the modification of those already 
established for use in the prevention of these diseases may be ex- 
tremely rapid. 

The Division, because of the nature of the products itith 
which it is concerned, performs a great deal of cooperative re- 
search with other components of the Public Health Service, members 
of the biological products industry, state laboratories, the Pan 
American Sanitary Bureau, and in the development of international 
biological standards with the World Health Organization. 

In addition to its other functions, the Division operates 
the blood bank in the National Institutes of Health Clinical Center. 
CONTROL PROGRAM 

The control program discharges the Division's licensing re- 
sponsibilities under the biologic control provisions of the Public 
Health Service Act. This Act requires that all products coming 
within the term "biological products" be licensed as a means of 
ensuring their safety, purity, and potency. This includes licens- 
ing of manufacturing establishments as well as individual products 
manufactured. The Division determines the eligibility of estab- 
lishments and of individual products for licenses on the basis of 
a review of the physical facilities for both the manufacture and 
testing of products, the scientific and professional qualifications 
of personnel, and the evidence of continued safety, purity, and 
potency of products under consideration. 



i :-.V. 



- k - 

The Division inspects each licensed establishment annually 
and maintains constant liaison with manufacturers of biologicals 
through frequent conferences. It conducts tests in its own 
laboratories in order to supplement or corroborate data submitted 
by manufacturers. In addition, it establishes and distributes 
physical standards used in both the production and testing of bio- 
logicals. 

Programs relating to two specific products, influenza vaccine 
and poliomyelitis vaccine, which have been of unusual interest during 
the past year because of their activity and their requirements for 
the interdigitation of control and research may be cited as illustra- 
tive of the problems which can be expected to face the Division of 
Biologies Standards from time to time. 
ASIAN STRAIN INFLUENZA VACCINE PROGRAM 

The Asian strain influenza program, which assumed national 
importance in 1957; involves both the control and the research po- 
tentials of the Division and illustrates the type of emergency 
which the Division must be prepared to meet. While influenza vac- 
cine is not a new product and additional strains have been added 
to the vaccine during the past 12 years, the situation confronting 
the Division and the manufacturers in the summer of 1957 differed 
from earlier ones. This situation involved a production goal of 
tremendous size complicated by an extremely limited time factor. 
Sample strains of the virus causing the epidemic in the Far East 
were furnished the manufacturers of influenza vaccine on May 22 



..•.•V1<F XO 



i X)P- 



- 5 - 
by the Division and were immediately placed under intensive study 
in order to determine the feasibility of the immediate, large- 
scale production of an effective vaccine. In the interest of 
expediency, potency testing procedures were modified, and the 
manufacturers, working on a round-the-clock schedule, were able 
to market an effective monovalent vaccine on August 12 — less 
than three months after samples of the new strain had been re- 
ceived. During the first four months of production, the Division 
tested and cleared for release 321 individual lots of influenza 
vaccine. 

Through the use of ad hoc advisory groups and the contin- 
uous close cooperation with the technical staffs of the manufac- 
turers, as well as other experts in the field, numerous technical 
problems were successively overcome and by mid-December of 1957 
over 6l million doses of Asian strain vaccine had been produced. 

Concurrently with this greatly expanded testing program, 
research was carried out on the development of new reference 
standards and improved testing procedures. These studies were de- 
signed with two objectives in mind. The first, and most pressing, 
was maximum production of a monovalent vaccine in the shortest 
possible time in order to meet immediate needs. The long-range 
goal was the production of a polyvalent vaccine containing the 
new strain in sufficient quantity to ensure adequate protection, 
and the concurrent development of standard safety and potency 
tests covering all components of such a vaccine. By December 1957 
the first of such polyvalent vaccines was in production. 



- 6 - 

While the immediate problems involving influenza vaccine 
and the Asian strain of virus will be solved prior to 1959; a con- 
tinuing influenza program must be maintained by the Division in 
order to meet future emergency situations which may result from 
the seeding of the new virus throughout the general population. 

The ability of the Division to meet this recent emergency 
without increase in funds or personnel emphasizes the importance 
of maintaining organizational and program flexibility. 
POLIOMYELITIS VACCINE PROGRAM 

During the first eleven months of 1957 the testing of polio- 
myelitis vaccine continued to represent a major activity of the 
Division. One hundred and seventy- five lots of vaccine were tested 
for safety in monkeys and in tissue culture, while potency deter- 
minations were performed on thirty-three lots in monkeys and sixty- 
six lots in chickens. By November 1957 the production and testing 
of poliomyelitis vaccine had reached the stage where "double testing" 
could be modified in favor of the procedure of testing individual 
lots of vaccine only when there is an indication of the need for 
doing so. This, together with the expected decrease in demand for 
vaccine in this country, should considerably lessen the testing 
workload during 1959« This permits the Division, while carrying 
out a realistic control program for the testing of poliomyelitis 
vaccine comparable to that conducted for other vaccines, to imple- 
ment its plans, as set forth last year, for devoting additional 



- 7 - 
effort to other aspects of poliomyelitis immunization which are in 
need of attention; e.g., selection of more suitable virus strains, 
development of new cell lines for tissue culture, and study of 
attenuated live poliomyelitis viruses. 

The Division continued to utilize the assistance of the 
Technical Committee on Poliomyelitis Vaccine and to maintain close 
cooperation with the technical representatives of industry, with 
attention being given to the problem areas both actual and poten- 
tial. As a result, several proposed changes designed to improve the 
vaccine are now being considered and will probably be effected be- 
fore the end of 1958. 

As a result of the Division's continued effort toward de- 
vising a more satisfactory potency test for poliomyelitis vaccine, 
a test has now been designed utilizing chickens instead of monkeys 
for potency determinations. This new test not only provides more 
precise results, but can be performed at considerably less expense, 
while obviating dependence upon Rhesus monkeys, the procurement of 
which is becoming increasingly difficult. The introduction of this 
test as a requirement is expected prior to 1959* 
RESEARCH PROGRAM 

Considerable progress has been made in the research program 
essential to the operation of effective biologies control during 
the past year. The Division has had some success in its efforts 
to recruit key personnel. For two years this has been one of the 



- 8 - 
most pressing problems of the Division. Several of the higher 
level positions have been filled, one vith an eminent virologist 
who will head research in the rapidly expanding field of biological 
products derived from viruses. 

Modification of requirements for double safety testing of 
poliomyelitis vaccine will permit further redirection of effort 
toward other problems in the virus field, including the following 
which are already under study: 

1. Procedures aimed at the in vitro assessment of the 
antigenic potency of vaccines have been developed. It has been 
found that the complement -fixing antigen content of vaccines and 
their antibody-combining capacity generally parallel their immu- 
nogenic potency in animals, the latter being the classical method 
for determining the potency of vaccines. The use of these in vitro 
methods may provide a rapid and relatively inexpensive method for 
following the effect of different steps in the manufacturing process 
on the potency of the final vaccine, a problem of concern to the 
producers. 

2. Each year Rhesus monkeys become increasingly difficult 
and more expensive to obtain. Two avenues are being explored to 
circumvent the necessity of using Rhesus monkeys for the testing of 
poliomyelitis vaccine, and possibly other viral vaccines. One is 
the use of monkey species other than the Rheusus. Studies with the 
African vervet monkey indicate that these animals are fully as 
susceptible as the Rhesus and provide kidney tissue culture cells 



- 9 - 
which yield equally large amounts of virus. The second is the 
study of continuous tissue culture cell lines which is being pur- 
sued in an effort to find lines which may prove even more sensitive 
to poliovirus than the monkey kidney cells presently used. 

It has been found that certain lines of rabbit cells may 
become susceptible to poliovirus in the laboratory, however, the 
rabbit characteristics of these cells seem to disappear and the 
cells are then indistinguishable by present methods from those 
derived from other species, including man. This observation has 
now been confirmed in a number of laboratories. Further work is 
necessary to characterize such altered cells before they can be 
considered satisfactory for production of vaccine for human use. 

3. Virus strains proposed for use in live poliomyelitis 
vaccine are now under study, so that satisfactory standards for 
production and testing of live virus vaccines may be applied in 
the event that such vaccines, which are experimental at present, 
become practical biologic products. 

h. Tissue culture methods have been studied with a view 
to the possible production and standardization of smallpox vaccine. 
Results have been encouraging. Bovine, avian, and Rhesus monkey 
cells yield equivalent amounts of virus; however, of those studied, 
the monkey kidney cell is the most sensitive indicator of the 
presence of virus. 

5. With the recent adaptation of measles virus to tissue 
culture, there is a strong possibility that a vaccine is achiev- 
able in the near future. Studies have been initiated to provide 



:!>'' 



T.VK 



- 10 - 

experience and information concerning the characteristics of the 
measles virus , with a view to the eventual development of standards 
and specifications for a satisfactory vaccine. 

# # * ¥t 

Standards for the safety, purity, and potency of vaccines 
for the prophylaxis of adenovirus infections were developed and 
promulgated this year. Samples of the vaccine, which is now on 
the market, are "being tested for safety in tissue culture and 
monkeys and for potency by inoculation of various animal species. 

With the constantly increasing use of blood and blood 
products, the Division's continuing research programs on the 
preservation and storage of blood assume increasing importance. 
Investigations are currently being conducted on the stability of 
normal serum albumin, effects of various chemical and physical 
agents on plasma, chemical characteristics and efficacy of various 
sterilizing filters, improved shipping containers, potency testing 
for diagnostic blood grouping reagents, evaluation of various 
blood products used in hemorrhagic conditions, low temperature 
storage of red blood cells, and the protection of donors against 
air embolisms and other hazards. 

A project of considerable importance to the many blood 
banks throughout the Nation is one on the evaluation of the various 
sources of blood banking errors. This long-rang project, which 
has been carried on for approximately one year, is designed to 
factually determine the extent of the problem, the possible reasons 
for the errors which do occur, and the development of preventive 
measures. 



- 11 - 

Part of the Division's long-range program on the develop- 
ment of more effective immunizing agents is a study designed to 
determine the enhancing effect obtained when certain of these 
immunizing agents are combined and where adjuvants are added. 
The role of some of the factors involved in this phenomenon is 
being studied using diphtheria and tetanus toxoids and pertussis 
vaccine as examples. 
NEW DBS BUILDING 

One of the main problems of the Division is the provision of 
adequate space in which it can efficiently conduct its functions. 
At present, the Division is occupying space which has been re- 
novated and altered in an effort' to meet the demands of isolation 
of the testing of vaccines and other products from the infectious 
agents necessary to the research program. 

Consequently, the areas occupied by the Division have 
encroached on research space urgently needed for programs of the 
other Institutes. Unsatisfactory situations thus exist for the 
present. However, these deficiencies will be met with acquisition 
of a new building, final plans for which have been completed. The 
present schedule contemplates construction starting this spring. 
It is anticipated that the approximate completion date will be 
in the latter part of calendar year 1959; with occupancy immedi- 
ately thereafter. 
FUTURE PROGRAM 

The Division plans to continue to place increasing emphasis 
on research basic to a sound control program, thus obtaining 
knowledge and data necessary to anticipate and meet problems and 



- 12 - 
to deal with them effectively. These plans do not call for a major 
increase in staff in the near future, but rather reflect an effort 
to build into the program further flexibility which will permit 
such shifts in emphasis as may be required, such as occurred 
during the past year. The Division was able to devote a consider- 
able amount of its resources and time to the problem of the Asian 
influenza vaccine emergency without requesting additional funds. 
Eased on these plans, the Division is not requesting any 
increase in funds or personnel for 1959 • It will request some 
increases in connection with the occupancy and operation of the 
urgently needed new building. This request will be timed to the 
construction schedule of the building. 



ATTACHMENT B 
DIVISION CF RESEARCH GRANTS 
INTRODU CTION 

The Division of Research Grants has administrative 
responsibility for the coordination and the management of the 
research grants and fellowship programs of the NIH and serves as 
a focal point of coordination and administrative assistance for 
the training grants programs of the several Institutes. Through 
the action of 27 Study Sections and of several ad hoc committees, 
the Division provides technical advice on applications for grants 
so that specific recommendations for action may be made to the 
nine National Advisory Councils, 

The growth and expansion of the Institutes' extramural 
research and training programs over the past decade reflects the 
intent of Congress to broaden and accelerate medical research as 
well as to increase scientific manpower. From 19^+6 through 1957; 
the Public Health Service, through the National Institutes of 
Health, provided continuously increasing research grant assistance. 
In Fiscal Year 1957 support was provided to 6,186 non-Government 
scientists in 572 research institutions and universities. During 
the period 19^6 - 1957; it also provided 8,000 research fellow- 
ships for research training in 338 institutions here and abroad. 
Through the training grant support, approximately 11,000 man- 
years of training were provided to younger scientists preparing 
themselves for specialized academic and professional careers. 



- 2 - 
Grants for the construction of health research facilities in 150 
institutions have been awarded in order to aid these institutions 
in increasing markedly the amount of space available for research 
in the medical schools and teaching hospitals of our country. 
Grants for Research 

An important function of the Division of Research Grants is 
to support a significant volume of research, principally in the 
basic biological and related sciences not falling within the respon- 
sibility of the categorical Institutes. It is the intent of the 
Division of Research Grants to bring as much as possible of this 
fundamental work to a point where its application to a specific 
problem can be made. This support must be continued and strength- 
ened in order to achieve sustained productivity and to provide the 
stimulating environment in which scientific "break-throughs" may 
be expected to occur. 

A good example of how fundamental research has led to 
important clinical findings is reflected in a project supported 
by the Division. It was initiated by a grantee of the St. Louis 
University School of Medicine, Dr. Alrick Hertzman, Professor of 
Physiology, who, as his work turned into "practical" areas, re- 
ceived thereafter categorical Institute support. His project was 
originally concerned with the development of methods for measuring 
circulatory changes in the extremities of animals and man. Experi- 
ments on animals revealed that surgical interruption of major 
sympathetic nerve trunks at their point of branching from the 



- 3 - 

spinal cord often failed to eliminate all sympathetic nerve activity 
in the region supplied by that nerve trunk. These observations led 
to a re- examination of the anatomy of the spinal cord and its 
branches in conjunction with physiological studies of the terminal 
distribution of the nerves in question. Subsequent findings were 
at variance with the "text-book" picture. These were manifest in 
marked variations from one segment of the spine to another, result- 
ing from the frequent separation of one or more fibers from a 
sympathetic trunk at levels above or below the main point of branch- 
ing from the spinal cord. 

Sympathectomy — surgical cutting of the branch of the 
sympathetic nerveous system -- would obviously fail to interrupt 
these nerve impulses from small abnormally placed fibers which now 
served as alternate routes for impulses which the operation was 
intended to eliminate. 

These findings accounted in anatomical terms for the 
"therapeutic failures" and "relapses" which many surgeons had 
encountered in the treatment of hypertension by sympathectomy and 
which also served to divert research attention away from surgery 
towards the field of "chemical sympathectomy." The term "chemical 
sympathectomy" refers to the use of certain hypotensive drugs 
which block certain nerve paths involved in the maintenance of 
"high blood pressure," Hypotensive drugs (or autonomic gang- 
lionic blocking agents) have now very largely replaced surgery in 
the management of this disease. 



- k - 

Recognition of this aspect of basic neuroanatomy has also 
made it possible to relieve intractable pain in certain patients 
by a second operation aimed at those fibers which lie outside of 
the primary nerve tract. In retrospect, this clinical application 
seems far removed from the original basic research which was con- 
ducted without reference to any particular disease. It is, however, 
only one of many instances where fundamental research, supported 
through the Division of Research Grants, has provided the necessary 
clues and stimulus to other research of clinical significance. 
Training Grants 

Training grants are intended to augment the Nation's supply 
of qualified scientific investigators by assisting in the establish- 
ment, expansion, and improvement of training programs in universities 
and other research institutions and in the support of trainees 
therein. Aid to the institution is provided by the following types 
of research training grants: 

1. Experimental Training Grants 

The Experimental Training Grants program, initiated in 
Fiscal Year 1957 and continued in 1958, will continue in 1959 at 
the $500,000 level. The program permitted 8 leading medical schools 
in 1957> and an additional 6 schools in 1958, to test various means 
of Identifying gifted medical students and thereafter giving them 
special research training while they are still in medical school. 
It is expected, upon their graduation, that they will provide a 
valuable pool of research-oriented physicians who will be eligible 
to undertake full-time academic careers without the necessity of 
taking additional formal research training. 



- 5 - 
2. Basic Research Training Grants Progr am 

Of special importance is the basic science training 
grants program, responsibility for which has been assigned to the 
Division of Research Grants. This program is specifically designed 
to support the basic science training functions in the training 
Institutions, and to provide additional urgently needed research 
trained personnel in such major shortage areas as pathology, phar- 
macology, genetics, anesthesiology, epidemiology, biometry, bio- 
chemistry, physiology, and other fields of the health related 
sciences. This training program will act as a "feeder" for the 
categorical Institute training programs, thereby serving strongly 
to increase their effectiveness within their special areas of 
primary responsibility. Grantee institutions receiving funds under 
the program will select and appoint individuals for predoctoral 
and postdoctoral training. 

3« Epidemiology and Biometry Training Grants 

The number of training programs in epidemiology and 
biometry has increased markedly until at the present time there 
are 31 programs in these fields, representing well over a million 
dollars annual investment. Of the 31 programs, 15 fall in biometry. 
The importance of these biometry training grants can hardly be 
overemphasized at this time of national need for mathematicians and 
biostatisticians. Nearly every graduate school in our country has 
one of more unfilled professorial positions available in the area 
of biometry. 



- 6 - 
Research Fellowships 

The research fellowships program presently has five major 
areas of interest: 

1. The research training of regular predoctoral and post- 
doctoral candidates for research careers. 

2. The support of scientists in the basic preclinical 
sciences through Senior Research Fellowships. 

3. The introduction of brilliant, highly motivated medical 
and dental students to research through the device of 
part-time student fellowships. 

h. The provision of opportunity for full-time research 
training for at least one year to outstanding medical 
and dental students who may elect temporarily to delay 
their formal professional training. 
5. Postdoctoral research fellowship support to citizens 
of the British Isles or Western Europe for advanced 
research training of at least one year with dis- 
tinguished scientists in our country. 
Regular Research Fellowships 

These awards are made generally in the fundamental fields 
of the biological sciences, such as anatomy, biochemistry, and 
physiology. Predoctoral awards usually result in the holder's 
receiving a doctoral degree in science; some of the postdoctoral 
candidates may also receive a second doctoral degree in one of the 
basic sciences. In Fiscal Year 1957> 83 regular fellowships were 
awarded; 69 are being awarded in 1958; and the program will continue 
at approximately the same level in 1959. 



- 7 - 
Senior Research Fellowships 

The Senior Research Fellowship program is helping to relieve 
the shortage of academic leaders in such fields as anatomy, behavor- 
ial sciences, "biochemistry, "biophysics, genetics, microbiology, 
pathology, pharmacology, and physiology. Now in its second year, 
these research fellowships are helping to stabilize support for 
92 highly promising scientists. These awards function as an effec- 
tive deterrent in preventing competent investigators in fundamental 
areas frommoving into the more highly remunerative clinical fields. 
Since the funds to support a Senior Research Fellow must be entirely 
additive to the university department's budget, each award frees 
the time of a teacher for research, with the result that the depart- 
ment has two professional staff people engaged in research and 
teaching for each award made. 

Approximately 50 additional Senior Research Fellowships 
will be awarded each year through the fifth year, at which time 
the program is expected to level off with annual support thereafter 
of approximately 250 additional research and teaching positions 
in the preclinical sciences. 
Post- Sophomore Research Fellowships 

Through these grants, superior medical and dental students 
have an opportunity to obtain research training prior to comple- 
tion of their professional degrees. In general, these fellowships 
are awarded to candidates at their natural break between their 
preclinical and clinical course work. This program provides 



;-•■■ Xii ■:':.; \ 



- 8 - 
full-time research training support for one to three years. In 
1958; a total of 165 Post -Sophomore Fellowships were awarded and 
the program will continue at the same level in 1959. 
Fellowships for Scientists in Other Countries 

Considerable progress has been made in the development of 
plans reported to Congress last year for the awarding of a limited 
number of postdoctoral research fellowships to outstanding medical 
research scientists in Western Europe. 

Through the able assistance of Dr. John R. Paul, Professor 
of Preventive Medicine, Yale University, the National Institutes of 
Health has completed arrangements with appropriate national research 
bodies in 12 Western European countries for collaboration in this 
program, including the initial screening and transmittal of appli- 
cations. These national research bodies are: 

Germany - Forschungs Gemeinschaft der Deutschen Wissenschaft 

France- Cultural Relations Committee on Foreign Affairs 

Switzerland - Fonds National Suisse de la Recherche Scientifique 

Italy - Consiglio Nationale delle Richerche 

Austria - Austrian Academy of Science 

Finland - Academy of Finland 

England - British Medical Research Council 

Norway - Norwegian Research Council for Science and Humanities 

Denmark - Universities Joint Committee 

Holland - National Health Research Council 

Sweden - Swedish Medical Research Council 

Belgium - Foundation Universitaire 

A total of 1^ applications are already under review and 25 

to 30 additional ones will be reviewed, Only those applications 

endorsed by the national research organizations will be considered. 

From such applications, 12 awards will be made in 1958. In 1959 the 

program is expected to continue at approximately the same level. 



- 9 - 

Recipients of these fellowships are encouraged to spend a 
short time at the National Institutes of Health in order to be 
acquainted with our facilities and give us advantage of their 
technical competence. Their principal training will for the most 
part be received from an outstanding American scientist in an 
appropriate research institution. It is expected that these awards 
will benefit both the European and United States' scientists through 
the mutual exchange of methods and ideas. 

Recipients are required to return to their home country upon 
the completion of their period of training. 
Effectiveness of Research Fellowship Training 

Dramatic evidence of the effectiveness of the Public Health 
Service research fellowship program has recently been provided in 
a study of the current interest and activities of research fellows 
who completed training between 19^6 and 1956. 86.5$ of these former 
research fellows reported that they are currently engaged in research 
in universities, medical schools, hospitals, or in publicly supported 
research institutions. A further analysis of the data in this study 
reveals that more than half of these individuals also combined 
teaching activities with research. 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Cancer Institute, 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"National Cancer Institute" 

The program of the National Cancer Institute, including 
intramural and extramural research, has reached new highs in 
scope, total effort and productivity in the past year. Plans 
for 1959 call for a budget of $55,923,000 to finance these 
activities. 

Current studies are substantially increasing our understand- 
ing of viruses as a possible cause of cancer. Epidemiology and 
environmental cancer research are also contributing data on cancer 
causation and incidence. 

Clinical investigations with the drug methotrexate in the 
treatment of choriocarcinoma have now been extended to include 
17 patients, one of whom has remained free of cancer for about 
30 months. Other new drugs undergoing clinical trial by Institute 
grantees include prednisone, prednisolone, and Mytatrionediol. 

The chemotherapy program is benefiting from the cooperation 
of the pharmaceutical industry, which is taking a leading role in 



'• .u.on.f 



■• ??*■-■■ '. -JX? 



-2- 

the search for anticancer agents. Chemotherapy continues to 
offer a good chance of finding effective means for controlling 
disseminated cancer. 

Research on the cytologic detection of cancer has been 
expanded to include, in addition to uterine cervical cancer, 
tumors of several other body sites, such as the lung, bladder, 
large bowel, and prostate gland. Cytology also provides valuable 
epidemiological data on the incidence of cancer among various 
population groups. 

For successful prosecution of its program, the Institute 
continues to aid in the training of young scientists in fields 
related to cancer research. 






OPENING STATEMENT 

*y 

Director, National Cancer Institute 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"National Cancer Institute" 

The year which has passed since I last appeared before this 
Committee to discuss the program of the National Cancer Institute 
has been productive and rewarding. Progress is being made on so 
many fronts that many of U6 feel we may be nearing a number of 
major breakthroughs in our knowledge of these diseases we call 
cancer. 

Thanks to the interest of this Committee and the Congress, 
our research efforts this year have reached new highs in scope, 
total effort, and productivity. Scientists in Universities sup- 
ported by Institute grants have developed sound research projects 
which this year will utilize all such funds available. The co- 
operation of the pharmaceutical industry with our chemotherapy 
program as envisioned by this Committee has become a reality. 
The use of exfoliative cytology in detection of cancer of body 
sites other than the uterine cervix is now under study in several 
locations. In our Bethesda facilities we have opened a new Pedi- 
atrics Unit to further our studies of leukemia and other cancers 
in children. I will report more specifically on some of the 



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- a - 

more exciting discoveries in- cur laboratories — particularly in the 
virus field. Our training programs -continue to prove successful 
in producing the professional personnel for future advances in 
"basic research and the control of cancer. 

Our plans for 1959 call for a budget of $55,923,000 
comparable to an operating budget of $55> 937^000 this year. The 
new phases of our chemotherapy and cytology programs will be in 
their first full year of operation. Research supported under 
grants and much of the research in our Bethesda laboratories will 
be along lines which have proved so rewarding in the past. At 
Bethesda the year should see a marked intensification of efforts 
to understand the role of viruses in the causation of cancer. 

I should like to present in more detail some of the aspects 
of our program to illustrate why we look to the coming year with 
such optimism. 

The four major categories of research conducted and supported 
by the Institute continue to be: l) the causes of cancer; 2) the 
characteristics of cancer ; 3) cancer detection and diagnosis; 
and k) cancer treatment. To illustrate the advances made in 
cancer research in the past year, I would like to mention a few 
of the important research findings. I shall begin with a brief 
summary of some of the results of our studies on the role of 
viruses in cancer causation. 



-3- 

VIRUS STUDIES 

The question of whether viruses cause human cancer has 
"been a subject of intensive research, and even controversy, among 
prominent medical scientists for the past 50 years. The story 
of the search for the relationship between viruses and cancer has 
all the elements of a good detective story. The only trouble is 
that we can't turn to the last page of the story to read the 
solution. 

The virus story concerns living cells, since cancer is 
believed to be a disease in which normal cells for some reason 
lose the property of growing in a regulated manner and instead 
grow wild and unrestrained. Knowledge of the complex structure of 
the cell is also still limited. But one of the most exciting 
discoveries about the innermost nature of the cell has been that 
a complex chemical, called nucleic acid, is a major constituent 
in every cell and plays a vital role in life processes. One 
type of nucleic acid, DM, is localized in the chromosomes- -the 
gene carriers — and is generally believed to be the actual genetic 
material. DNA appears to be the template, or blueprint, for the 
reproduction of living matter, with its special characteristics 
from one generation to the next. This same nucleic acid is also 
a major component of some viruses, and it is this component which 
seems to determine their disease- causing potential. 



p/-fc.<~ 



The suggestion that viruses might he in some way linked 
with the production of cancer was first advanced in 1903; shortly 
after the discovery of viruses. Because at that time no cancer 
had been demonstrated experimentally to result from inoculation 
with a virus, the suggestion was not taken seriously. A few 
years later in 1910, Dr. Peyton Rous of the Rockefeller Institute 
described a transplantable fowl cancer, which became known as the 
Rous sarcoma. In 1911 he described a filterable agent which was 
separable from the tumor and capable of transmitting it. This 
agent has been the subject of many investigations since that time 
and is now commonly known as the Rous sarcoma virus. 

In the years since 1911/ other viruses causing cancers 
in chickens, pheasants, ducks and other fowl, as well as mice, 
frogs, rabbits, deer and other animals, have been discovered. 
Today, it is generally accepted that there are virus- induced 
tumors in animals and plants, but there is still little evidence 
that cancer in man is associated with viruses. Yet the' belief 
that viruses cause human cancer is growing. Outstanding virol- 
ogists like Dr. Wendell M. Stanley of the University of California 
are making statements like the following: "I believe the time has 
come when we should assume that viruses are responsible for most, 
if not all, kinds of cancer, including cancer in man, and design 
and execute our experiments accordingly." 



-5- 

So the stage is set and the time seems ripe that some 
major breakthroughs will occur in this area of cancer research. 
Against this background, permit me to relate to you the results 
of two National Cancer Institute studies which we believe to have 
great significance. In one, a long term quantitative study was 
made of the manner in which the Rous sarcoma virus produces cancer 
in domestic fowl. The investigator measured, for example, how 
long it takes a tumor to appear after the virus is injected, how 
quickly the tumor grows, how much virus can be extracted from the 
tumor tissue, and how long it takes for the tumor to kill the host. 
His results revealed certain facts and relationships which are 
contrary to scientific opinions and assumptions that have been 
held for a long time regarding the role of tumor viruses in pro- 
ducing cancer. He found that all the responses measured were 
related to the dose of Rous sarcoma virus used to induce the 
tumor. Consequently, the results of this study have produced two 
new concepts of the host-virus relationships. These state that 
l) the Rous sarcoma virus is itself the direct cause of the cancer 
and is not merely the agent that acts indirectly by "triggering" 
some inherent characteristic within the host; and 2) the biological 
properties of the tumor are related to the dose of Rous virus, and 
that, therefore, the absence of recoverable viruses in tumor tissue 
extracts does not necessarily rule out the classification of a 
tumor as having a viral origin. 



- 6 - 

In the other study, one of our scientists was attempting to 
confirm a report that cell -free extract of mouse leukemia produced 
leukemia in newborn mice. Oddly enough, leukemia did not result, 
but an unusual type of tumor which occurs spontaneously in mice 
only rarely was produced. This was a tumor of the parotid 
(salivary) gland. Attempts to transplant this tumor by injecting 
new-born mice with cell-free extracts prepared from the parotid 
gland tumors were not successful. But when, in collaboration 
with scientists of the Division of Biologies Standards, cell sus- 
pensions of parotid gland tumor tissue were grown in tissue 
culture for about two weeks and then the supernatant fluids from 
the cultures were injected into newborn mice, this substance took 
an explosive course and resulted in development of multiple pri- 
mary tumors. All mice that developed such tumors had many types 
of tumors including primary parotid gland tumors, tumors of the 
thymus, adrenals and mammary glands. 

The investigators consider that the fluids contain a virus- 
like substance which has the capacity to produce cancers in many 
parts of an animal's body. In addition, they found that it has 
the capacity to produce cancers in noninbred strains of mice; 
that is, to cross the so-called immunogenetic barrier. This is 
extremely important research, because it marks the first time 
that such a wide range of malignant growths have been produced 
experimentally by a cell-free filtrate having virus- like properties. 

If we are able to achieve similar results with material ex- 
tracted from human tumors — and if this material should prove to be 



m 



-7- 
a virus — we will indeed have made a major breakthrough. If it should 
be thus established that certain forms of human cancer are viral in 
origin, it might then be possible to immunize man against the disease, 
It is worthy of note that in one study, supported by a grant from 
the National Cancer Institute, a vaccine has been produced which 
protects 80 percent of mice from a virus-caused disease resembling 
leukemia. We do not know whether other scientists will be able to 
duplicate these results or whether they will have application to 
human cancer, because we have no proof that human cancer is caused 
by a virus. But, virus research is constantly adding to our store 
of knowledge; it may possibly enable us one day to develop a power- 
ful weapon against human cancer — an anticancer vaccine. 

OTHER RESEARCH ACTIVITIES 
Causation 

A grantee of the National Cancer Institute has demonstrated 
that it is possible to inhibit the cancer-producing effect of 
methylcholenthrene, a well known chemical carcinogen, by adding 
orotic acid to the diet of experimental animals. This is an 
important development in testing our theory that certain cancers 
of environmental origin are preventable. 

In another study, an Institute scientist has found that 
tumors of the testes induced in mice by administration of a fe- 
male sex hormone can continue to grow when the stimulus is re- 
moved or when bits of the tumor are transplanted into new hosts. 



- 8 - 
Until now, such tumors have "been considered dependent for further 
growth upon continued hormonal stimulation. In other words, re- 
sults of this study suggest that induced testicular tumors of the 
mouse have limited dependence upon hormonal stimulation for develop- 
ment and can achieve independence whan the hormone is removed from 
hosts carrying primary tumors or when the tumor is transplanted 
into new hosts. 

Characteristics 

Institute scientists have reported the finding of a mouse 
tumor which closely resembles human multiple myeloma, a form of 
hone cancer. This finding may permit the study of this model 
of a human cancer in experimental animals which would be of tre- 
mendous value not only in understanding of the natural history 
of this disease hut also in efforts to develop effective thera- 
peutic measures against it. 

Institute scientists have isolated and identified for the 
first time a structural unit in cells of the liver and spleen 
which has proved to he ferritin, the principal iron storage com- 
pound of the animal body. This was done hy electron microscopy, 
which is assuming increasing importance in the study of cancer. 

A method of separation of soluble proteins from human 
"blood serum by chromatography permits the study of disease 
states including cancer. Some of the isolated proteins have 
"been defined only in a physicochemical way, and their biological 
significance remainf to he determined. Enzymes may he concen- • 
trated-even purified-in the same way, and the possibility that 



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- 9 - 
filterable viruses may also "be concentrated by these techniques 
is being explored. 

Treatment 

Last year I told the Committee about the apparent suppres- 
sion of a malignant tumor in four patients following administra- . 
tion of a drug — methotrexate — by National Cancer Institute 
scientist. The cancer was choriocarcinoma, a solid tumor of the 
uterus which occurs very rarely after pregnancy. As of now, 17 
patients have been treated for this disease by drug therapy, and 
we are extremely encouraged by the outcome. Not only did the 
primary uterine tumor apparently disappear in these patients, 
but so did secondary lesions in the lungs. These are the first 
reported cases in this country of the suppression of a solid 
malignant tumor by drugs alone. One of the women has remained 
totally free of cancer for about 30 months, a testament to the 
effectiveness of this therapy. 

In another grant- supported study, the administration of 
large doses of prednisone or prednisolone, newly synthesized 
compounds which are chemically related to cortisone, has pro- 
duced clear-cut remissions in both children and adults with 
acute leukemia. Of the 18 patients treated in this study, com- 
plete remissions occurred in 5 adults and partial remissions 
were observed in 6 adults and children. 

Experiments on the treatment of cancer in mice have shown 
that sensitization of the tumor by administration of anticancer 
drugs augments the effectiveness of radiation therapy. A group 



?-'kV' 



- 10 - 

of National Cancer Institute grantees observed that mammary 
tumors treated by both X-rays and antimetabolites quickly began 
to show regression. This effect was still apparent at the end 
of the observation period. More tumors treated by both X- irradia- 
tion and anticancer agents regressed completely than did tumors 
treated by either X-rays or chemicals alone. The investigators 
conclude that the limit of curability of cancer by radiation 
is no longer determined by a lack of sufficiently powerful 
radiation sources. They further suggest that the sensitization 
of a tumor by biochemical means appears to be an important method 
of increasing the response of malignant cells as compared with 
that of normal tissue. 

Total removal of the right lobe of the liver in order to 
cure cancer has been successfully performed by a grantee of the 
National Cancer Institute. The patient was a 14-year old girl 
who presented the typical picture of sudden onset, relatively 
little stomach and intestinal disturbance, and a large abdominal 
mass. Surgical exploration revealed a cancer of the right lobe 
of the liver, which was at the time considered inoperable. The 
tumor was heavily irradiated, causing a 50 percent reduction in 
size with considerable increase in the firmness of the tumor and 
surrounding liver tissue. It was then determined that the affected 
lobe could be safely removed by surgery. The operation was 
carried out, and the patient was released 19 days later in 
apparently good physical condition. 



- 11 - 

The problem of administering effective doses of radiation 
to cancer patients without producing undesirable systemic side 
reactions demands intensive investigation in both clinical and 
preclinical areas. Administration of therapeutically effective 
doses without these reactions has been accomplished in treating 
superficial cancers, especially mycosis fungoides in human 
patients, with a three-million electron volt electrostatic 
generator in the Clinical Center. Study of tumordose relation- 
ships in X-ray therapy of cancer reaffirms the concept that the 
volume of tissue included in the target area may be a serious 
limiting factor in determining the dose that may be given with- 
out complications. A drug which reduced the deleterious effects 
of total body X- irradiation in experimental animals is being 
studied for its possible influence on therapeutic irradiation. 
Some General Aspects of Research 

A technique recently developed by members of our staff now 
permits accurate, quantitative measurement of radiation exposure 
to the whole body surface regardless of whether the exposure re- 
sults from therapy or from accidental causes. The technique is 
applicable only in persons whose heads have been exposed to 
radiation and involves microscopic examination of scalp hair 
roots. The investigators found that damage to the hair roots 
correlates precisely with the amount of radiation exposure and 
the interval between exposure and examination. Copies of the 
paper in which this procedure is described have been requested 



■t'-SSV- 



- 12 - 

by the United Nations Scientific Committee on the Effects of 
Atomic Radiation. 

We are continuing an intensive study of environmental 
cancer with much of the work "being accomplished through field 
studies. The purvey of the health of uranium miners is contin- 
uing, About 3>000 miners have been examined at least twice. 
A few cases of lung cancer were detected. However, the 
studies must be carried on much longer before any significant 
data can be developed. The National Cancer Institute is collab- 
orating with the Air Pollution Medical Program of the Public 
Health Service in a two-year study of the carcinogenicity of air 
pollutants. Investigations will also be continued on occupational 
exposure that may increase the risk of industrial workers to dif- 
ferent types of cancer. A study of the relationship of environ- 
mental factors affecting mothers and the risk of leukemia develop- 
ing in their children is continuing to produce important, 
although preliminary, findings. 

It is to be expected that certain aspects of cancer 
research may be emphasized for varying periods. However, research 
is so interdependent that one area cannot advance far without 
contributions from advances in other areas. Because biochemistry 
is fundamental to several research areas, it is clear that re- 
search in this field should be encouraged. Viruses, as pre- 
viously stated, are becoming increasingly important both in 
cancer causation and treatment. New techniques for studying 



- 13 - 
viruses and their life processes in cells should he extended to 
human cancer. Why does cancer attack some people and not 
others? Research on the part played by heredity in the suscepti- 
bility of a cell to become cancerous and in its ability to in- 
fluence cellular growth and reproduction must be pursued and 
expanded. Recent research has suggested the possibility that 
antibodies can be induced against cancer in man. This, as I 
mentioned before, suggests that eventually we may be able to 
vaccinate people against some forms of cancer. Obviously, this 
work should be pushed ahead as rapidly as possible. These are a 
few of the aspects of cancer research which will receive partic- 
ular attention and be explored to the fullest possible extent in 
fiscal 1959. 

CHEMOTHERAPY 
The chemotherapy program now constitutes approximately 
ten percent of the total NIH budget. If one includes funds being 
expended from other sources, cancer chemotherapy research probably 
accounts for approximately ten percent of the total national 
health research effort. We regard this as appropriate since with 
the tools and information now at hand, chemotherapy appears to 
offer a good chance to find an effective means for controlling 
disseminated cancer. This guarded optimism appears to be shared 
by many companies in the pharmaceutical industry which have 
recently begun to invest substantial sums of stockholders' funds 
in cancer chemotherapy research. 



i- ■;../; ■.. 



- 14 - 

The appropriation of funds for industrial contracts in 
the current fiscal year has permitted the establishment of a 
major research and development contract program with industrial 
concerns. The contracts support in-plant screening programs, 
research on methodology, or pilot plant production of otherwise 
unobtainable materials in quantities sufficient for clincal 
trial. A few contracts are for the synthesis of new chemicals 
but for the most part industry is bearing the full cost of 
developing new materials. 

This greatly increased industrial participation so 
eagerly sought by the National Cancer Institute and the Congress 
has necessitated the amplification of DHEW patent policy to meet 
the special problems related to industrial research contracts. 
Under this policy the Government is in a position to finance 
the testing of industry- developed chemicals without charge to 
the company and without loss of proprietary rights in the com- 
pound to the company. The result has been a major increase in 
company funds invested to develop new compounds. The patent 
policy also provides for situations in which the company i6 
willing to undertake drug development but does not feel justi- 
fied in investing company funds. In such instances the patent 
policy permits the company to own patents covering inventions 
made in the course of the contract, subject to certain limi- 
tations designed to protect the public interest. These limi- 
tations include a royalty-free license to the Government for 
government uses and a "march-in" clause which permits the 



- 15 - 
Government to license competitors on a royalty-free "basis if the 
inventing company, after a reasonable period of time, fails to 
supply the market with adequate quantities of the drug at high 
quality and reasonable price. Although some objections have 
been raised to certain criteria for "marching in" and some 
details of the method of licensing, industry appears to regard 
this policy as fair and equitable; it affords greater rewards 
to the company willing to finance its own drug development with- 
out unduly penalizing the company which seeks Government support 
for its drug development research. 

We are optimistic that the participation of the pharmaceu- 
tical industry will greatly accelerate progress in the program — 
progress which could not be achieved without the skills, 
facilities and investments which are now being made in order to 
locate new drugs and to isolate the active substance in the anti- 
biotic filtrates or "beers." 

One aspect of the chemotherapy program requires special 
mention. The program has grown in what can be characterized 
only as "growth in an explosive manner." We are quite proud that 
despite this Dr. Endicott, with the advice and counsel of super- 
ior groups of scientists, has built soundly. However, the 
program needs and in fact demands a period of evaluation and 
adjustment. 

It is already apparent that it contains imbalances which 
were an inevitable result of rapid growth. The screening, we 
believe, with our industrial contracts, will be adequately 



- 16 - 
covered for some time to comet The chemical workup of potenti- 
ally useful compounds from antibiotic beers is also well covered, 
organic synthesis of new compounds and larger scale synthesis for 
clinical trial have been provided, systematic work on the develop- 
ment of more generally useful testing is under way, and a broad 
base for clinical testing has been established. 

However, no adequate provision has been made for the most 
difficult step of all, i.e., intermediate workup prior to clini- 
cal trial. This deficiency has received special attention during 
the current year, but at least another year will be required, I 
believe, to satisfy the need fully as it continues to emerge. 
This is essentially a requirement of time rather than money. I 
have cited this as one example of a program imbalance in chemo- 
therapy; there are others. 

The budget that is before you, therefore, provides for 
the Cancer Chemotherapy Service Center and its advisory groups 
to be given a period of time for a "shakedown cruise" within 
the present dollars available. This level of support is needed, 
but a period of time is necessary for sound program adjustment 
so that funds may be utilized in the most economical and effective 
manner . 

A detailed presentation of the chemotherapy program is be- 
ing submitted separately for the record. 



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-17- 
CYTOLOGY 

In past years the Committee has heard extensive reports on 
our progress in developing the cytologic test as a case-finding 
tool. I should like now to "bring the cytology story up to date. 

There are ten cytologic research units in operation "by the 
National Cancer Institute and three additional screening projects 
financed by grants. Ten of these 13 are uterine cytology projects, 
and the other three- -plus one to he established this year — are for 
investigation of the possibility of applying cytology to the detec- 
tion of cancer of other body sites. 

It is as yet too early to say whether cytology will be as 
useful in detecting other forms of cancer as it is in detecting 
cancer of the uterus. We can only hope that this technique will 
enable the physician to establish an earlier diagnosis and thus 
gain better management of cancer os such sites as the lung, urinary 
bladder, large bowel and prostate gland. 

Uterine cytology is, of course, valuable as a case-finding 
procedure; but it has also proved to be extremely useful as a means 
of gathering epidemiological data on the incidence of uterine cancer 
among differing groups of women. During the year, a cytology project 
was established in cooperation with the International Ladies' Garment 
Workers' Union in New York City from which we should be able to get 
interesting and valuable epidemiological data. In this study, it 



-18- 
may be possible to compare the incidence of uterine cancer among 
women of several ethnic groups — Italian, Irish, Jewish, and Puerto 
Rican. Incidentally, in an epidemiological study it has been 
observed that cancer of the uterine cervix is nearly four times as 
common among non-Jewish women of New York City as among Jewish women 
of either New York City or Israel. We do not know the explanation 
for this phenomenon, but the observation may provide leads which 
will help to explain variations in the incidence of uterine cancer. 

Another cytology project has been established at the Women's 
Medical College of Pennsylvania where women employed in industry 
will be studied. Here too we hope to be able to gather information 
on incidence as well as to detect the disease in its earliest most 
curable stages. 

This is another program which, like chemotherapy, has been 
developed to a stage where we believe a leveling off is needed for 
a "shakedown" period. We have a sufficient number of pilot projects 
established in which to continue our observations on the efficacy of 
the cytologic test as a case-finding technique and an aid to early 
diagnosis of uterine cancer. We also have, or will have, as I have 
indicated, several projects for research on the application of this 
test to the early detection of cancer of other body sites. The cyto- 
logy program is continuing for the time being at its present required 
level of support in order that funds may be utilized economically 



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-19- 
and effectively for research which we are confident will continue to 
develop useful procedures for employment of the cell examination 
test in public health and medical practice. 

A detailed statement on the development and status of the 
cytology program is also being submitted separately for the record. 

OTHER DEVELOPMENTS 

In addition to the programs I have singled out for special 
mention, there are, of course, many and varied activities of the 
National Cancer Institute which are no less essential to the success- 
ful prosecution of our mission to reduce mortality from cancer. 

In order for research and medical practice to function effec- 
tively there must be rapid and dependable communication. Among 
scientists this is accomplished by the publication of research findings 
and discussion of them in conferences and seminars. To serve these 
purposes the National Cancer Institute continues to publish its 
Journal on a monthly basis. Our people attend scientific meetings, 
conduct seminars, and confer with visiting scientists from all over 
the world. 

Communication of Information and educational materials to 
the lay public also continues to be an important Institute activity, 
for the layman must be alerted to the necessity of cooperating with 
his physician if cancer is to be effectively controlled. 

In both professional and lay information and education activi- 
ties the Institute cooperates freely and effectively with the American 
Cancer Society and other groups and interests devoted to the cancer 
problem. 



-20- 

The training of scientists in fields related to cancer 
research is another important activity of the National Cancer 
Institute, The success of cancer research depends largely on the 
supply of specially-trained, imaginative research scientists who 
are willing to enter the field of cancer research and who are 
academically and professionally qualified to do so. The shortage of 
such personnel is a serious problem in cancer research as it is in 
all scientific fields. We are aware that the problem cannot he 
solved overnight. The training of a research worker is a slow and 
expensive process. To help meet this shortage of scientific personnel, 
the National Cancer Institute provides financial support to promising 
scientists so that they may obtain training in their chosen fields. 

Institute funds are also used to improve instruction in the 
diagnosis and treatment of cancer received by students in medical, 
dental and osteopathic schools, and for the training of young clinicians 
who wish to specialize in cancer work. 

One of the most important developments of the past year was the 
establishment of a Board of Scientific Counselors to advise the 
Institute on the development of its intramural research program. We 
are fortunate in having as Chairman of this body the distinguished 
Nobel Prize winner, Dr. Wendell M. Stanley of the University of 
California, who recently completed a term of office as a member of 
the National Advisory Cancer Council. 



-21- 
CONCLUSION 

The total program of the National Cancer Institute, oper- 
ating at its present level, is making an impact on the cancer 
problem. The close relationship of laboratory research to clinical 
research at Bethesda, the widespread and diversified character of 
our grant- supported research, and the scope of the cooperative chemo- 
therapy program, with its emphasis on industrial cooperation, are 
providing a momentum which was unknown in the cancer field a few 
short years ago. Research developments of quite recent months- - 
some of which I have mentioned today--are serving to indicate the 
places where important breakthroughs may be expected in the not too 
distant future. These breakthroughs may lead to better understanding 
of the origin and nature of cancer; they may open direct and short 
paths to drug cures; they may point the way to widespread prevention 
of cancer through immunization. No matter what form these blessings 
may take, and no matter from what direction they may come, we can 
be certain that they will be the results of research. 

I appreciate very much the attention that the Committee has 
given to this discussion of our activities. I shall be happy to 
answer any questions and assist in any further discussion that the 
Committee may desire. 



K8 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Institute of Mental Health 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

"Mental Health Activities, Public Health Service" 

For Mental Health Activities in 1959 > the budget proposed 
is $37,697,000. 

Much progress was made during the past year in the Institute's 
continuing research, training, and community services programs. 
In addition, advances in such special areas as psychopharmacology, 
mental retardation, drug addiction, alcoholism, and aging have 
brought new knowledge and improved methods of applying that know- 
ledge through organized public mental health programs. 

The Institute's training grants and research fellowships 
programs have added substantial numbers to the reservoir of trained 
professional personnel neodad to do research and to provide the 
many needed mental health services. Grants are also supporting the 
long-term development of outstanding investigators and teachers 
who are devoting their careers to mental health, 

In the field of research, the Institute has allocated a 
substantial amount of its facilities and personnel for work on 
schizophrenia, including, in addition to clinical investigations, 
organization of a long-range multidisciplinary study of the biology 



- 2 - 
of schizophrenia. Important advances in the Institute's laborator- 
ies were made during the year in such areas as an understanding of 
the contribution of the organic factors to pleasure, pain, anxiety 
and fright, effects of brain lesions on behavior, effects of 
parent-child relations on child development, sociological factors 
in aging, and addictive properties of new drugs. 

The Institute's grant- supported research program continued 
to embrace a broad range of biological and behavioral studies, with 
appropriate emphasis on such key subjects as mental retardation, 
schizophrenia, psychopharmacologic approaches to study of mental 
illness in general, and mental health problems of later life. 

The Psychopharmacology Service Center has served to encourage 
and stimulate much needed work on the use and effects of the newer 
drugs, in addition to that conducted and supported by the Institute 
itself. Opening of the new research facility at St. Elizabeths 
Hospital will enable the Institute to expand its clinical studies 
in psychopharmacology as well as in schizophrenia. 

The Institute is also developing new programs to assist in 
the rehabilitation of mental patients who are benefiting from the 
new drug and other therapies. Mental health projects grants are 
supporting studies designed to improve the treatment and speed the 
discharge of mental hospital patients. In some cases, studies are 
being supported to explore methods of providing service which may 
obviate the need for hospitalization. 



S.l. 1 



- 3 - 

In addition, consultation and assistance have been pro- 
vided to State mental health programs in a variety of important 
areas, including: analysis of data essential to evaluation of 
new psychotherapeutic programs; establishment of alcoholism and 
drug addiction control programs; school mental health; programs 
for the mentally retarded; and mental hospital problems. 

Plans for fiscal year 1959 emphasize the continuing adjust- 
ment of the Institute's activities and programs to new and emerging 
patterns of mental health needs, and the increasing use of broad 
interdisciplinary research attacks on mental illness, both in the 
intramural and extramural programs. 



OPENING STATEMENT 

by 

Director, National Institute of Mental Health 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"Mental Health Activities, Public Health Service'' 

Mr. Chairman and Members of the Committees 

In a moment, I would like to discuss some important 
emerging patterns in the mental health field. But first, I will 
summarize the fiscal aspects of our budget as it is before you e 
For mental health activities in the fiscal year 1959 the 
budget proposal that is before you requests an appropriation of 
$37,697,000. This compares with $38,376,000 available for these 
same activities in fiscal year 1958. The apparent decrease is 
largely technical. The decrease is made up of $500,000 from 
grants for research projects due to the termination of the special 
three-year study authorized by the Mental Health Study Act of 1955 
(Public Law 182, 84th Congress), and $179,000 from direct operations 
due chiefly to non-recurring expenditures. 

Last year there were substantial savings in research grants 
partly due to the fact that the Psychopharmacology program did not 
get started as fast as anticipated,, This year it is anticipated 



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- 2 - 
that most of the funds appropriated for this purpose will he 
spent. The Training Grant program has proceeded as planned; the 
increase in 1958 of about $1,300,000 has been utilized to develop 
essential areas in the growing program for developing professionally- 
trained manpower. The most notable change in the instramural pro- 
gram has been in the cooperative project with St. Elizabeths 
Hospital; the structural changes in the new facility are almost 
complete and the scientist who was recruited to direct this 
activity has taken charge of the laboratory and is proceeding 
ahead of schedule with his staffing. 

The request for mental health activities for fiscal year 
1959 includes $11,902,000 for research grants, $5^6,000 for research 
fellowships, $13,300,000 for training grants, $^,000,000 for grants 
to the States for mental health activities and other preventative 
and control services. It also includes $5*808,000 for intramural 
research, $591*000 for the review and approval of grants, $70,000 
for in-service training activities, $1,221,000 for professional 
and technical assistance activities, including the work of the 
Psychopharmacology Service Center, and $259*000 for administration 
of the Institute. 

These funds are requested for expenses necessary to carry 
out the provisions of the Public Health Service Act as amended with 
respect to mental diseases. 



- 3 - 
SCME EMERGING PATTERNS IN THE MENTAL HEALTH FIELD 

The experience of the National Institute of Mental Health 
over the last decade has greatly broadened its concept of the 
problems which are related to mental health. At the outset the 
major tasks were properly viewed as increasing the availability 
of adequate treatment, enlarging and improving the supply of 
trained mental health personnel, and mounting an expanded research 
program designed to solve many of the unanswered questions about 
mental illness. The Institute has made considerable progress in 
all of these areas, 

In addition, though, other problems have become identified 
as wholly or primarily within the mental health field, One such 
problem is the application of psychiatric and mental health 
approaches to the alleviation of persistent social problems such 
as delinquency, retardation, and drug addiction» Then, too, we 
have become increasingly concerned with the prevention of mental 
illness and the promotion of mental health as a positive asset of 
man, and initial steps were taken to explore how the basic agencies 
and organizations of the community tend to increase or decrease the 
probability that the individual can achieve and maintain a high 
degree of mental health. To illustrate further— the Institute 
recognized the need to know how disasters and other extreme cir- 
cumstances affect mental health and how the mental health status 
of people determines their ability to deal with these occurrences. 



- 1+ - 

Developments such as these, serving to enlarge the horizons 
of mental health as a field, have caused the Institute to give 
careful attention to the area of program development. During our 
early years, emergent problems were handled as they appeared, but 
more recently the Institute has developed systematic methods for 
determining program areas which will require attention if this 
Institute is to carry out its total mission. The major device 
has been intensive staff work designed to clarify the problem, 
followed by planned coordination of various Institute programs 
directed to different aspects of the problem, and buttressed by 
research designed to supply answers where lack of knowledge 
deterred adequate approaches and programming^ 

The range of questions that have been studied in this way 
has been great. A large amount of work has been done on the pro- 
blem of rehabilitating the mentally ill patiento Studies of the 
effect of the school and work situation on mental health have been 
initiated. The drug addict, juvenile deliquent, mentally retarded 
child, and the alcoholic have received attention. Major efforts, 
both intramural and extramural, have gone into the field cf psycho- 
pharmacology. The psychological factors in accident causation and 
individual and group reaction to disasters have been studied. For 
the future there are additional problems that we know must be 
tackled, such as family disorganization and suicide. The results 
of these program development activities have been reflected in all 
of the operating programs of the Institute— research, training, and 
community services. 



- 5 - 
The areas that have been illuminated by these problem- 
defining techniques appear diverse and in some cases almost 
unrelated, but in fact they fall into four well defined groupings: 

1. The prevention or reduction of disability in pathologic 
or deviant populations (the delinquent, alcoholic, the 
clinically ill groups, especially the schizophrenic); 

2. Processes affecting the mental health of large groups 
or entire communities (mental health education, child 
rearing practices, aging); , 

3t Processes affecting the mental health of specific 
populations in organizational settings (schools and 
the work setting); 
k. Mental health aspects of traumatic or stressful events 
in various populations (accidents, disasters, epidemics, 
etc. ) 
The early work in these areas ; plus the fact that the areas 
of program development do form a pattern, make the Institute feel 
that it has made much progress in bringing its continuing programs 
in research, training and community services to bear upon the pro- 
blem of public mental health and that future orderly progress can 
be made to increase the contribution of mental health not only to 
the specific problems of illness but also to a large, number of 
related problems. 



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- 6 - 

Some New Understandings of the Bases of Normal and Impaired Human 
Functioning 

There has been little agreement among people generally and 
even among research workers on such questions as whether human 
ability or diability is inherited or acquired, whether disordered 
behavior rests upon organic or life experience factors, and whether 
people grow old psychologically, physically, or both. The important 
fact is that hereditary influences and organic factors are properly 
viewed only as conditions of development. Except for the extreme 
case, they are not as limiting as previously thought. The organic 
factors are not presently subject to much change or manipulation 
in the individual; but the environmental factors are subject to 
control and have tremendous potential effects which are just now 
receiving recognitions 

It appears now that some meaningful things can be said about 
these problems. It is common knowledge that inherited charac- 
teristics and organic factors are involved in every aspect of a 
man's body, mind, or functioning. It has long been known, too, 
that as the individual develops and as his body changes, so does 
his behavior change. Today, however, it is becoming increasingly 
apparent that there is no simple one-to-one relationship between 
organic factors and the psychological functioning of the individual. 
Severe organic deficit is, of course, associated with badly impair- 
ed behavior and development. Short of such crucial defect, however, 
such factors as the situation in which one exists, the experiences 
he has, and the amount and kind of human interaction and support he 
has are of extreme importance to his psychological development. 



■f{ • ;.;•."■ i 



- 7 - 
This conclusion comes from several areas of study,. There 
was a time when intelligence was thought to "be a fairly constant 
attribute of an individual. There were bright children, average 
children, and dull ones. It was thought they would remain what 
they were at first. It was then discovered that orphans who were 
presumed to be dull became much brighter when adopted into good 
and loving homes, while those who remained in the institutions 
appeared to get even more dullo These studies were almost ignored 
for a time. Later, other workers followed children from normal 
homes for their entire childhood. They found that the brightest 
infant was not necessarily the brightest first grader. They 
found children who became progressively brighter and those who 
grew dull. It began to appear that what happended to the child 
affected his mental growth. He was born with a nervous system 
and an ability to learn from experience. How fast he learned and 
how much depended upon many things. Today we are inclined to view 
intellectual measures, especially in children, primarily, as indi- 
cations of mental growth to date. The child may begin to get 
brighter or duller at any time. It appears now that the degree 
to which he is accepted and stimulated by others to achieve may be 
highly important in affecting his final level of mental development. 
It makes good sense, therefore, to talk about practices which 
maximize mental growth and those which retard it. It does in fact 
appear reasonable to say that improved child-rearing practices and 
educational advances can raise the achievement levels of all of • 
our children except those with extremely severe organic defect. 



- 8 - 

At the other end of the life span, there are comparable 
results derived from study of the aging process. Some people 
become senile as they grow old and others do not. For a long 
time it was thought that these differences depended upon the 
amount of cerebral arteriosclerosis that had developed. Sur- 
prisingly, though, post mortem studies show that some people 
who were alert and vigorous until time of death show considerable 
physical change of the brain and that some very senile-acting 
people have fairly "young" brains. Again there are limits. The 
important point is that behavior is not tied tightly to organic 
characteristics. Those who retain a place in life and a pattern 
of interaction with people, who have interests, activities and 
responsibilities, tend to show relatively few of the behavioral 
signs of senility. Those who step aside or are pushed aside, 
who lose their place in affairs, who really have "nothing to do" 
tend to behave like senile people. In other words, even the 
impaired and aging human body can perform pretty well when it needs 
to do so and when there are strong social and emotional satis- 
factions for doing so. 

The effects of trauma give the same picture, even when 
brain tissue is involved. The ability of people to compensate for 
many kinds of bodily injury and loss is well recognized, but now 
it appears that surprising ability exists to overcome even the 



- 9 - 

effects of permanent brain damage. Except for extreme cases the 
human "being seems to regain function, even though he cannot 
regenerate actual nerve cells. The brain is apparently very- 
adaptable, and relearning in the brain-injured individual is 
often astounding -- when such relearning has meaning for the 
person in his total life situation. 

It is of some importance to compare studies of animals 
and men in this connection. By and large, animals do not show 
as much ability to regain function after brain damage as does 
man. It is in the higher mammals, such as chimpanzees, that it 
does occur, and here, too, it appears to be partially related to 
the social context as it is in man. 

In the clinical area there are findings that indicate 
that the schizophrenic patient can operate at near normal levels 
under optimal conditions of social stimulation, although he may 
regress again if the favorable circumstance deteriorates. This 
fact justifies the large amount of effort the Institute has 
expended upon this aspect of the schizophrenia problem, in 
addition to its extensive work on the problems of clinical care 
and the biology of this illness. 

What has been said here is of great significance. It 
represents no effort to deny the reality or importance of organic 
and biological factors in determining the way man grows, develops, 



- 10 - 
behaves and achieves. It has become clear, however, that social 
stimulation and support, motivational influences and the psycho- 
logical needs of the individual also determine the level to 
which the person will develop, the degree to which he will over- 
come organic deficit (whether it be congenital or acquired), and 
the degree to which he realizes his potentialities (whether he be 
normal or in some way handicapped). It means that perhaps only 
a few people reach anything like their optimum level of achieve- 
ment and development. 

The fact that one's behavior is not a mere reflection of 
his physical and organic nature is extremely fortunate. It means 
that handicap of a physical and organic nature is not always as 
limiting as might be assumed. By learning how human interaction, 
motivation, and the social circumstances of life can contribute 
to development and recovery, much hope exists even for those cases 
of congenital or acquired organic defect that do not yield to con- 
tinuing efforts to prevent them. It means also that normal people 
have potentialities for productiveness and usefulness much greater 
than has been thought before. It means that the promotion of 
mental health as contrasted with treatment of the ill or the pre- 
vention of clinical disorder is a reasonable prospect to which the 
psychological and social sciences can address themselves with . 
realistic hopes for success. 



: r 



-li- 
lt is conclusions of the kind reported here that make 
exciting and interesting such tasks as rehabilitation, work with 
the retarded, and efforts to alleviate the problems of aging. 
Results will not pour in overnight, but the Institute feels that 
the program development areas outlined above represent ones in 
which great promise exists because of the kinds of research 
findings that have been reported and which are continuing to 
accumulate. The remainder of this statement contains a resume 
of the Institute's work in these areas, together with some of 
the more important developments in research, training, and 
community service activities. 

TRAINING ACTIVITIES 
The work of improving the quality and the quantity of 
trained professional personnel needed for mental health research a 
and services continued at full pace during the past year. A 
special report of the Institute's training program from 19^8 to 
1957 ) is being prepared at the request of the Congress. This 
report will provide details about the major objectives and 
accomplishments of the Institute's training activities. A 
major purpose of this program has been to train people for leader- 
ship in research, teaching, public service and administration, and 
community mental health work. Responses from approximately 3100 
of the 38OO individuals who have received support under the trainee- 
ship program from 19^8 to 1956 show that between 75 and 80 percent 
are now occupied in one of these important mental health careers. 



- 12 - 

There has "been increasing recognition of the need to develop 
still more broadly trained "biological and behavioral scientists to 
conduct important research and to contribute their skills through 
teaching and service in the major mental health problem areas. As 
one means of meeting this need, the Institute is now preparing to 
supplement its research fellowship program by providing training 
grants in any area of psychology where it is demonstrated that the 
individual will contribute through research or through services to 
public mental health programs. This will mean increased support 
of training for developmental or child psychologists, social psycho- 
logists, physiological psychologists and psychopharmacologists. 
Such people, once they are trained; not only will find careers in 
essential areas of research, but will be able to contribute to the 
solution of pressing mental health problems such as those encounter- 
ed in use of the tranquilizing drugs and in the area of school 
mental health. 

The Institute's mental health career teacher program, 
initiated in 1956 as a means of encouraging outstanding men and 
women to choose academic careers as educational leaders in the 
mental health disciplines, is now operating on a firm basis. 
Thirty career teachers in psychiatry, clinical psychology, psy- 
chiatric social work, and psychiatric nursing are currently being 
supported. 



- 13 - 

Two new training programs were initiated in 1957 and are 
continuing in 1958. One, a senior stipend program, is designed 
to help a limited number of outstanding individuals, currently 
in teaching, research or administrative work, to secure advanced 
mental health training on an interdisciplinary "basis. Five indi- 
viduals are now receiving such senior stipends, in addition to 
10 individuals receiving advanced research training through the 
special research fellowship mechanism. The other new program is 
aimed at providing basic science students with research training 
in the mental health disciplines. Sixty-five chemistry, pharma- 
cology, physiology, endocrinology, and other science students are 
now receiving this training. This is in addition to the $5^6*000 
being spent in support of approximately lh6 predoctoral and post- 
doctoral students in the research fellowship program. 

Funds requested for fiscal year 1959 will enable the Insti- 
tute to maintain the present level of support to training Insti- 
tutions. 

RESEARCH 

The Institute has continued to move forward in the intra- 
mural research work conducted with its own staff and facilities 
and in its support of research through grants to scientists through- 
out the country c Highlights of the accomplishments of this research 
work are presented in a separate document. Funds are requested to 
continue these research programs at substantially the same level 
as in fiscal year 1958. 



- 11+ - 

Biology of Schizophrenia 

The Institute has reallocated a significant share of its 
intramural research funds to develop a systematic study of the 
biology of schizophrenia, which remains the biggest problem area 
in the field of mental illness. Though many positive findings 
about the nature of schizophrenia have been contributed by every 
biological discipline, no pathological change is generally accepted 
as characteristic of the disease or as fundamental to the disease 
process. Studies of uniovular twins strongly suggest a genetic 
element in a large proportion of schizophrenia. There is some 
evidence of EEG abnormality, but little evidence of endocrinological 
or circulatory changes. In the field of biochemistry, there has 
been much emphasis on protein and amino acid metabolism. However, 
hypotheses (advanced during the past year) that a disordered 
metabolism of epinephrine or an abnormally high proportion of 
ceruloplasmin are related to schizophrenia were disproved by an 
Institute investigator, who demonstrated that these factors are 
related to the patients' blood level of ascorbic acid, and are 
thus a function of diet rather than of mental illness. 

What is needed is a comprehensive and integrated study of 
physiological changes correlated with schizophrenia. Up to now, 
there have been two principal impediments to research on the 
biology of schizophrenia. One has been the fact that diagnosis of 
the disease is entirely clinical and based on symptoms. The samples 



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- 15 - 
of patients chosen for study may actually have included examples 
of different diseases with a common symptomatology. Another 
major problem has been the inability to control non-disease 
variables. For example, control groups in biological studies 
of schizophrenia have often been selected from among individuals 
who differ from the patient group in many ways other than the 
mere absence of mental illness. 

With the new research techniques, the new leads, and the 
new sophistication about research methodology built up by the 
contributions of all previous investigations, the time is now 
propitious for a major effort in research on the biological 
aspects of schizophrenia. To this end the Institute's Laboratory 
of Clinical Sciences has been preparing and is now geared to under- 
take a long-range multidisciplinary program of studies in this 
field. It will attempt to discover how the schizophrenic differs 
from the normal person, the etiology of these changes, and ways 
in which the process can be reversed. 
Adult Psychiatry 

The Institute's adult psychiatric research work has continued 
to be concentrated on the basic psychiatric problems of schizophrenia* 
These studies have brought new knowledge about the nature of family 
and other environmental influences contributing to the develop- 
ment of psychiatric disturbances. Experimental treatment methods 
and new ways of managing patients have been utilized in investi- 
gations aimed at altering the course of the disease and promoting 



- 16 - 
recovery. One group of studies has led to preliminary hypotheses 
ah out the nature of familial influence on the development of 
schizophrenia. These hypotheses will serve as the focal point 
for further research on families of schizophrenics and neurotics, 
and on larger and more varied samples of families,, including 
those of normal individuals. The Institute's clinical research 
workers have also continued to seek better understanding of the 
factors influencing normal personality development and behavior. 

Additional work in clinical psychiatry and in the behavioral 
sciences is being planned and will be initiated in the Institute's 
new Clinical Neuropharmacology Research Center which will be 
opened at St. Elizabeths Hospital this year. Utilization of this 
unique facility not only will permit the application and testing 
of findings, but is also expected to generate new hypotheses, 
L aboratory Research 

The laboratory research at the Institute continues to 
accumulate specific and highly specialized findings that feed into 
a thorough understanding of mental illness. These findings are 
highly technical but highly valuable to the research worker and 
the skilled therapist. Studies of biological methylation, amino 
acid metabolism, and comparative biochemistry have advanced under- 
standing of the biochemistry of mental and neurological disease. 
Physical chemists are investigating various aspects of nucleic 
acids which appear to have an important role in memory, heredity, 
growth, reproduction, and many other interrelated aspects of health 
and disease. 



•'-■ 'i: 



- 17 - 

Researchers in the Institute's experimental animal 
laboratories, studying the effects of brain lesions on social 
behavior of primates, have discovered important differences in 
the way in which similar lesions affect monkeys and chimpanzees. 
The work of this- laboratory indicates that the social behavior 
of animals following brain damage may depend not only on the 
location and extent of the damage, but also on the nature of 
the animal's social environment before and after the operation. 
This finding has important implications for the treatment and 
rehabilitation of humans. 

One Institute neurophysiologist has developed a refined 
and more accurate technique for measuring the electric potential 
of nerve tissue. Another neurophysiologist, studying neuronal 
integration in the monkey, has explored the regions concerned with 
pleasure and compulsive activity, negative emotions and pain, 
anxiety, and fright. During the past year the Institute opened 
a new section on limbic integration and behavior which will study 
brain mechanisms fundamental to psychology, psychiatry, and 
neurology. 
Research on Alcoholism 

In its own research laboratories, the Institute is carrying 
on a large number of studies on biology and human development which 
have relevance to the problems of alcoholism. The Institute's 
Addiction Research Center, in particular, is studying physiological, 
organic, psychological, and social aspects of the problem. It was 



\'i - ;■•.:?' 



- 18 - 
•this Center which first demonstrated the physiologically addicting 
properties of alcohol when consumed in excessive quantities. In 
addition, Institute grants are supporting research investigations 
on biochemical and psychological aspects of alcoholism, and on 
clinic and rehabilitation programs for alcoholics. Because the 
use and abuse of alcohol is highly influenced by cultural and 
social factors, the alcoholic cannot be understood as an isolated 
individual; he must be understood as part of a whole complex of 
alcohol usage patterns, A study of alcoholism in this context is 
now being planned by one State, and the Institute is collaborating 
by providing consultation and assisting with research design. 
Research on Drug Addiction 

During the past year the Institute's Addiction Research 
Center at Lexington, Kentucky, found that three of five new anal- 
gesics tested had sufficient addiction liability to justify limiting 
their distribution in accordance with the Harrison Narcotics Act. 
The Center continued its studies of normorphine, a drug which has 
proved useful in counteracting accidental opiate poisoning and in 
simplifying withdrawal from morphine addiction. Since normorphine 
has the least addiction liability of any drug in the morphine 
series, and since tolerance to it develops relatively slowly, it 
is being studied very carefully in the continuing search for an 
effective, non-addictive analgesic. 



- 19 - 

The Addiction Research Center is continuing its work on 
chronic barbiturate and alcoholic intoxications, and on the bio- 
chemistry, neurophysiology, and neuropharmacology of addiction. 
The metabolism of morphine is being compared with that of nor- 
morphine, and plans are underway to study changes in epinephrine 
and norepinephrine (critical hormones released by the brain and 
central nervous system) during cycles of addiction. 

Work on the psychology of addiction includes an attempt to 
develop tests which will permit the accurate measurement of such 
subjective factors as pleasurable effects of different classes of 
drugs. A lever-pressing test for rats was developed to measure the 
reduction in anxiety caused by analgesics and their relative potency. 
It was found that morphine totally abolishes anxiety in anticipation 
of a painful stimulus. 
Research on Aging 

A major problem of older persons in our society, aside from 
economic and health problems, is the problem of loneliness. Most 
older persons do not have enough to do, and this affects their 
mental health as surely as do physiological changes. Institute 
investigators from 12 different laboratories, who for the past two 
years have been making an intensive study of .30 healthy aged men, 
are turning up findings that indicate psychological processes 
occur independent of changes in the biology of the nervous system. 



'•>.'_ -J>* 



^ni- 



- 20 - 

There are many reports of older persons who function normally 
although they have the same neuropathological processes as those 
who die of senile dementia. The mental health problems of older 
people are directly related to their ability to make adjustments 
that may differ widely from those they have been accustomed to 
make throughout their lives. Whether they can do so depends upon 
the opportunities offered by the community as well as the pre- 
parations they have made for their later years. The Institute 
therefore is studying the socio-environmental factors in aging 
and is carrying on a multidisciplinary program of activities that 
relates the mental health problems of aging to those of human 
development in general. 

To date, out of fiscal year 1958 funds, 17 research grants 
in aging are being supported for a total of $535,117. Among the 
grants awarded last year was one for the establishment of a 
center for aging research at Duke University which will permit 
a university -wide concentration of facilities and talents on 
fundamental research in this area. The center will train and 
interest investigators to do work on aging, and serve as a 
regional resource to disseminate useful information about better 
health and care for the aged and to provide scientific knowledge 
about aging to State and local governments and private groups. 
This project is being supported jointly by the National Institute 
of Mental Health and the National Heart Institute. 



J.UV; 



lai) 



■i ' '■••• 



- 21 - 

Studies on aging in the Institute's own laboratories 
have demonstrated a slowing in response with advancing age that 
is independent of motivation, and an increased latency in all 
voluntary responses which point to changes in the central nervous 
system. Investigations indicate the possibility that senile 
nervous diseases are characterized by decreased ability to in- 
hibit previously established responses. In other words, older 
people can learn, but it is harder for them if they have to do 
some "unlearning" first. New knowledge about the neurophysio- 
logical mechanisms controlling sensory "input" into the nervous 
system possibly has significant implications for understanding the 
relationship between learning, perception and experience. Insti- 
tute scientists working on an interdisciplinary study of cerebral 
metabolism are also making substantial contributions to the phy- 
siology of aging. Other research workers are conducting collabo- 
rative studies with other Institutes and the aging program of the 
National Institute of Mental Health is being coordinated with the 
activities of the National Institutes of Health's Center for Aging 
Research and the aging program of the Department. 
Grants and Research Fellowships 

Research work being supported by the Institute embraces the 
many biological and behavioral sciences in which clues must be 
sought for the causes of mental illness and for more effective 
treatment and preventive measures. Some grantees are conducting 
basic studies on the functioning and structure of the brain, 
brain chemistry, the relation of physiological processes such as 



- 22 - 

blood pressure and heart rate to "behavior, psychosomatic reactions, 
and the effects of very early learning (the so-called "imprinting" 
process) to later behavior. Others are studying the mental health 
aspects of such social problems as juvenile delinquency, retard- 
ation, and alcoholism. Many clinical studies on schizophrenia 
and other mental and emotional diseases are also being supported. 
To date this year, 123 projects totalling $2,89^,000 are directly 
related to the problems of schizophrenia; almost half represent 
psychopharmacological approaches to this major problem. In addition 
89 basic studies in such areas as neurophysiology, biochemistry, 
psychology, and sociology which have relevance to an understanding 
of schizophrenia are also being supported in the amount of 
$1,686,000; one-third of these fall in the area of psychopharma- 
cology. 

In addition to supporting individual research projects, 
the Institute is providing long-term support for proven investi- 
gators who are concentrating on key mental health areas, and is 
supporting major interdisciplinary team research work. One 
example of this is the center for aging research at Duke University, 
Another example of long-term support is a major five-year grant 
awarded last year to the University of Michigan and the Ypsilanti 
State Hospital for a program of basic neurophysiological and 
psychopharmacological research. Combining research and clinical 
facilities, this broad approach holds promise for advances in the 
diagnosis and prognosis of mental illness. 



:i ' 



- 23 - 

The research fellowship program continues to provide valuable 
research training for individuals in all fields of biology, medicine , 
and the behavioral sciences as they relate to problems of mental 
health and illness. In 1958; approximately 1^6 students are being 
given advanced research training at both the predoctoral and post- 
doctoral levels, including ten scientists who are receiving advanced 
research training through the special research fellowship mechanism. 
It is planned to continue this level of support in 1959« Infor- 
mation received from a follow-up study of the ^9 individuals 
supported under the research fellowship program from 19^8 through 
1956 shows that Q6rfo of the former fellows are now engaged in re- 
search work. 

The mental health career investigator program, which was 
established in 195^ to assist in opening research careers to 
qualified young psychiatrists and scientists in related fields, 
and which provides three to five years of support for full-time 
research and further development of research skills, is now sup- • 
porting 17 such individuals, with an additional 5 under active 
consideration for support out of 1958 funds. These individuals 
are selected from among the most promising and talented young 
scientists in the country; all are currently engaged in mental 
health research and plan to continue in these endeavors after ter- 
mination of their grants. A number have already been approached 
to fill important research positions and it is believed that all 
give high promise of making significant research contributions in 
the future to our understanding of mental illness. 



- 2k - 
Biometrics Research and Consultation 

Druing the past year, the Institute's staff of biometricians 
developed new techniques for gathering and analyzing data on trends 
in the movement of mental hospital and clinic populations. As 
more new therapeutic programs (drugs, use of day and night hospitals, 
half way houses, open hospitals, etc ) and treatment facilities 
are introduced into hospital and community programs, the task of 
obtaining data on people under treatment becomes increasingly 
important in order to assess the effectiveness and value of these 
treatments. The task also becomes increasingly difficult and com- 
plex, and data derived from separate treatment facilities, such as 
public mental hospitals and clinics and psychiatric services in 
general hospitals, become increasingly difficult to interpret. The 
Institute therefore will intensify its work with State mental health 
and State mental hospital authorities to develop statistical report- 
ing programs that will coordinate basic data on patients under 
treatment in all known psychiatric facilities in their jurisdictions. 



- 25 - 
PS YCHOPHARMAC OLOG Y 
Psychopharmacology Service Center 

Organized in the fall of 1956 to meet the needs posed by 
the rapid increase in the number of psychopharmacologic agents 
and their widespread use, the Institute's Psychopharmacology Service 
Center has, in a little more than a year, established a sound organi- 
zation for advising on, coordinating, and stimulating needed research 
in this field. In addition to its services in connection with drug 
studies in hospitals, the Center and its advisors are stimulating 
and assisting in studies of drug effectiveness on neurotic and 
other nonhospitalized patients. Investigators are being assisted 
with research problems on an individual basis, but the Center also 
plans to stimulate research by providing assistance and consider- 
ation to groups of scientists who may wish to conduct coordinated 
research in special areas. 

Solutions are being sought to a number of key problems, such 
as (l) how accurately to measure change in patients treated with 
the new drugs; (2) the influence of environmental factors, aside 
from the drugs, on the outcome of therapy; and (3) ways of shorten- 
ing the time needed to reach definitive results in a study, as well 
as ways of assuring that meaningful reports of studies will be made 
available to other investigators as rapidly as possible. 



i.w.y.Gis 



- 26 - 
Support of Research in Psychopharmacology 

In addition to work being done "by the Institute itself, 6° 
research grants in the field of psychopharmacology are being sup- 
ported for a total of $1,536,868. Another 3^ projects totalling 
$775,000 are pending review at the March meeting of the National 
Advisory Mental Health Council. The research supported includes 
basic and clinical studies of drug mechanisms and effects; attempts 
to synthesize new psychopharmacologic agents; psychological studies 
of drug action in man; biochemical mechanisms of drug action; and 
investigations of some of the basic biochemical activities of the 
nervous system as a means of understanding the nature and optimum 
usefulness of these drugs. 
Research in Psychopharmacology at the Institute 

Institute research in this field includes electrophysio- 
logical studies of drug action which have shown alearcut differences 
between the effects of hypnotic and ataractic drugs on the cerebral 
cortex. Other animal studies indicate that centrally acting drugs 
which appear to depress activity in the brain-stem impair perfor- 
mance on manual tests; this is significant since it differentiates 
between cortical and subcortical subgroups. In another attempt to 
study behavioral effects of psychopharmacological agents, an Instjr 
tute scientist has devised a visual discrimination test for experi- 
mental animals which clearly shows the effects of a number of drugs 
and will be extremely useful in the study of behavior in general. 



- 27 - 
Clinical psychologists at the Institute are comparing the effects 
of such drugs on intellectual, motor, and perceptual skills in 
normal individuals and in schizophrenics. Other workers at the 
Institute are attempting to assess the effect of the patient's 
social "background on his response to drugs, and the extent to 
which improvement in mental hospital patients in drug studies is a 
result of changed ward environment or of the drugs. 

The new research facility at St. Elizabeths Hospital will 
provide a clinical laboratory for controlled large-scale trials of 
pharmacotherapeutic agents and for intensive studies of drug action 
in normal man in various types of mental illness, with special 
emphasis at this time on schizophrenia and the depressions. The 
impact of pharmacotherapy on existing services in the mental hos- 
pital, and the need for new rehabilitation measures and for increased 
contacts between hospital and community will be studied. 
Outlook for Future Work In Psychopharmacology 

From the basic and clinical research done thus far, two 
major problems have emerged which require additional time for 
solution. There are not enough sound research workers in adequate 
clinical settings to permit rapid expansion of clinical work in 
psychopharmacology. This points up the urgent need for training 
such personnel. The other major problem is the inadequate under- 
standing at the present time of the diseases being studied. For 



- 28 - 
example, drugs with the same effect on a particular biochemical or 
neurophysiological mechanism in the body may have different effects 
on behavior, while drugs with the same clinical action may affect 
a given mechanism differently. Behavior effects are complex patterns 
of change, depending on the drug administered, the environment, the 
patient's life experiences, and even the activities of the observer. 
The Institute therefore is requesting funds to permit exploratory 
work and evaluation at the present level for a year or two, after 
which necessary adjustments will be made in the program prior to 
further expansion. 

MENTAL HEALTH OF CHILDREN 
Child Development 

The Institute has been conducting a broad range of normal 
child development studies, including the effects of social environ- 
ment on learning, the effects of family and community influences on 
general development, comparative studies of babies in normal homes 
and in institutions, the relationship of mother's personality to 
the personality and development of children, and the effects of 
individualized attention on responsiveness in infants. 

Institute investigators have devised a means of objectively 
measuring attitudes of parents toward children and child rearing. 
This test, known as the Parental Attitude Research Instrument, is 
being used in our laboratories and in laboratories throughout the 
country to study the relationships of such attitudes to parent-child 



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!,:.'...;■ '■'■■> 



- 29 - 
relations and to child development. It has already shown some 
interesting correlations "between parental attitudes and emotional 
and social adjustment of children, including children's activities 
and intelligence scores and may play a role in the complicated 
problem of predicting personality development. 
Delinquency and Emotional Problems 

Support of research on juvenile delinquency continues to he 
an important Institute concern. Twenty research projects 
totalling $600,^03 have received support to date in Fiscal Year 
1958. A clinic in Boston, assisted by a mental health grant, is 
making an intensive diagnostic study of hyperaggressive, incon- 
trollable boys and their families. Other centers, with the aid of 
grants, are attempting to develop improved techniques for diagnosis 
and treatment. One center is studying a group of 50 delinquents who 
had come before the juvenile court during 1957; and another is 
concentrating on the effects of the family and social situation. 

During the past year, the Institute opened its new Children's 
Treatment Center and transferred to it the group of emotionally 
disturbed boys who had been under study at the Clinical Center. 
The new treatment center is a cottage-type residential facility 
where the children, who have now recovered to the point where they 
can attend school and lead a more normal life, are being studied in 
terms of the therapeutic milieu. In the meantime, new groups of 
children with other types of severe emotional disturbances are 
being studied in the Child .Research Branch's Clinical Center ward 
facilities. 



- 30 - 

Institute researchers working with hyperaggressive children 
find that these children (l) display a unique kind of pathology 
that combines aspects of childhood neuroses and psychoses; (2) show 
intense anxiety about the possibility of being dependent; and (3) 
have severe - problems in developing a sense of their role in society. 
Progress is being made in analysis of learning disturbances in these 
children, and in developing and improving therapeutic techniques. 
Mental Health in the School Setting 

Because of the school's crucial role in building the foun- 
dation for individual mental health, the Institute has increased its 
efforts in this direction and is now supporting a large amount of 
research on school mental health. Recently a major study was initi- 
ated in which a teacher -training institution will investigate the 
psychological aspects of the events and processes that take place 
in the classroom, the school, and the community to determine their 
effects on the children's mental health and on the educational ■ 
efforts of the school. 

The Institute is developing plans, in its training program, 
to encourage the addition of more functional knowledge about the 
behavioral sciences in the preparation of teachers to help them 
deal with emotional problems encountered in a cleasroom setting. 
An Institute psychiatrist is devoting full time to consultation with 
schools, assisting them in applying knowledge currently available. 



- 31 - 
Working in cooperation with the State Board of Health and Department 
of Education, the Institute has helped one State set up a case-find- 
ing program, to demonstrate ways and means by which communities can 
detect and manage minor mental health problems in school children. 

Investigators at the Institute's Mental Health Study Center, 
conducting a follow-up study, have found that reading disability 
is related not only to the child's intellectual development, but 
even more so to his emotional difficulties, and that these diffi- 
culties usually presage a high drop-out rate from school. The goal 
of this and other similar studies is to learn how the schools can 
best minimize the effects of emotional problems already present 
and prevent the development of others. 
Mental Retardation 

To date, during fiscal year 1958; the National Institute 
of Mental Health has supported a total of 19 research grants 
directly in the field of mental retardation for a total of 
•1^93; 536. These investigations range frcm studies of amino acid 
metabolism and phenylketonuria and the role of heredity, to stud- 
ies of diagnostic and learning problems in retardation. 

A number of basic research investigations in the Institute's 
laboratories are concentrated on the biochemical and neurophysio- 
logical aspects of retardation. In addition, NIMH scientists are 
cooperating with research workers from other Institutes, including 
the National Institute of Neurological Diseases and Blindness and 
the National Institute of Arthritis and Metabolic Diseases. 



- 32 - 

Institute funds are being used to train professional person- 
nel needed to do research on retardation and to work with the 
retarded. Consultation and assistance are being provided to 
States and local communities in the establishment and development 
of programs for the mentally retarded, and a portion of Federal 
grants-in-aid funds is being allocated by the States for special 
projects on mental retardation. 

CARE OF THE MENTALLY ILL 
Mental Health Projects Grants 

New trends in psychiatric care stress the importance of 
hospital-community interrelationships not only in helping patients 
readjust following hospitalization, but also in developing services 
that obviate the need for hospitalization or that may help make the 
hospital experience more therapeutic. Under its mental health pro- 
jects grant program, authorized by Public Law 911 passed by 
Congress in 1956, the Institute has begun to support whole new 
groups of studies and demonstrations in the treatment of the mental- 
ly ill. Forty-four projects for a total of $1,305>3O6 have thus 
far been granted out of the $2-million available for this purpose 
in fiscal year 1958 • Studies are being supported under this pro- 
gram in 18 States, Hawaii and Puerto Rico. The range of subjects 
is broad and includes such important areas as a day hospital pro- 
gram for psychotic children, use of public health nurses in the 



!>. wm< 



- 33 - 
supervision of convalescent psychiatric patients, a study of 
alternatives to hospitalization, providing comprehensive psychiatric 
services in a geographically isolated area, referral services in a 
large urban area to provide immediate psychiatric help for indi- 
viduals who threaten suicide, and the use of practical nurses and 
other nursing personnel as a way of overcoming the shortage of 
professional nurses in State hospitals. Funds requested for fiscal 
year 1959 "will permit the support of this program at the current 
level. 
Hospital Consultation .Service 

In addition to this new program the Institute has acceler- 
ated its consultation services to mental hosptials. Through this 
assistance new program ideas and improved patterns in the care of 
mental patients are beginning to become widespread. Some of the 
more important of these are the establishment of psychiatric 
facilities in general hospitals, and the development of aftercare 
facilities and programs operated by hospitals or by voluntary 
and public agencies in the community. 
Rehabilitation Studies 

The Institute's vital concern with the problem of rehabili- 
tation of the mentally ill continues to increase as new and more 
effective treatment methods increase the rates of discharge from 
mental hospitals. A pilot study of rehabilitation and rehabili- 
tation personnel supported by the Institute at a State Hospital 



- 3^ - 
has shown that chronic patients tend to become adjusted to the 
hospital and resist rehabilitation efforts. Another Institute- 
supported study on the post-hospital experience of the mental 
patient is exploring the important area of bridging the gap between 
hospital and community. The past year saw the publication of an 
important work in this field, The Patient and The Mental Hospital , 
which comprises the research contributions made by outstanding 
authorities at the Institute-supported conference on socioenviron- 
mental aspects of patient treatment in mental hospitals. 

During the past year scientists on the Institute's staff 
have begun studies in this area. This work will be expanded in the 
coming year when the Institute will have additional facilities in 
its Clinical Neuropharmacology Research Center being opened at St. 
Elizabeths Hospital, 

ASSISTANCE TO STATE PROGRAM DEVELOPMENT 

The Institute is continuing to expand its general technical 
assistance and consultation activities to State and local mental 
health programs, in addition to its special services to mental 
hospitals, school mental health activities and work on aging, 
alcoholism, and other mental health problem areas. Institute staff 
are cooperating with a wide variety of national and international 
agencies and organizations on such diverse problems as mental health 
in rural areas, services for aged persons, juvenile delinquency, 
and mental retardation. Institute regional staff, working with 
the Southern Regional Education Board, were instrumental in setting 
up the first regional program to train school psychologists. 



- 35 - 

The program of technical assistance projects was continued 
to assist States with particular mental health problems and to help 
them develop new program areas. A course on community mental health 
programs for State-level staff will be started this year, and ■ -■.'•? 
central consultation services on research and evaluation of mental 
health programs have been established. 

Stimulated and assisted by grants-in-aid and technical 
assistance from the Federal Government, the States have been making 
substantial progress in the development of mental health programs, 
A number of States are also expanding their training and research 
activities in mental health. During the past year, continuing the 
steady trend of the past 10 years, the States increased the total 
funds budgeted for mental health program activities. 
Alcoholism Control Activities 

As the focus of Public Health Service activities in the field 
of alcoholism, the National Institute of Mental Health has been inte- 
grating work in this area into all of its various programs, and has 
helped to stimulate State and local community alcoholism control 
activities. Some States use part of their Federal grant-in-aid 
funds for alcoholism programs, A full-time consultant on alcoholism 
provides guidance and technical assistance in the development and 
expansion of such activities, and the consultant staffs in the 
regional offices assist in serving as a source of information and a 



- 36 - 
clearinghouse on problems of alcoholism. The Institute has "been 
cooperating with other interested organizations, and has supported 
research conferences in the field. Early in calendar year 1958; 
the Institute, in cooperation with the Bureau of State Services, 
plans to call a National Conference on Alcoholism. 
Addiction Control Activities 

Research during recent years on the social and psychological 
apsects of addiction has demonstrated that social "background must 
be considered if treatment and rehabilitation of the addict are to 
be successful. As a demonstration of how this new knowledge can be 
applied to a control program, the Institute during the past year 
established a Narcotics Addiction Demonstration Center in New York 
City to work with patients discharged from the Public Health Service 
Hospital in Lexington, Kentucky. The Center helps former addicts 
utilize local health and welfare facilities, and provides psychiatric 
consultation to these agencies so that they can better meet the 
needs of the ex -patients. In the few months the Center has been 
open, it has succeeded in securing cooperation from practically 
all the community agencies involved. This is a big step forward, 
since the tendency has been to let the former addict shift for 
himself — with relapse the almost inevitable result. The Center is 
also studying readdiction rates, and social and psychological factors 
that make for "cure" or relapse. 



- 37 - 
CONCULSION 
Significant progress has been made during the past year in 
mental health research, in training needed personnel, and in develop- 
ing and expanding services. Important advances have also been made 
in defining and enlarging basic understanding of key mental health 
problems. The program and approach of the National Institute of 
Mental Health are now helping to develop increasing and more effect- 
ive tools for the prevention and control of mental and emotional 
illnesses. 



SUMMARY OF OPENING STATEMENT 

"by- 
Director, National Heart Institute, Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"National Heart Institute, Public Health Service" 

Mr. Chairman and Members of the Committee: 

Heart research and related activities of the National Heart 
Institute program have "been strengthened during the year. Areas 
of special promise have been emphasized, such as atherosclerosis 
(hardening of the arteries), high blood pressure, research in 
aging, epidemiology, training to increase scientific manpower, 
and the application of knowledge. 

The 1959 request is for $35,936,000, the same amount as 
the current fiscal year, 1958» This will permit the consolidation 
of gains of the past year and further progress in such areas as 
those mentioned above. Some 1,227 research projects will he 
supported through grants in 1959* 

The research fellowships request of $1.1+ million will 
provide k-26 awards to help alleviate the continuing scientific 
manpower shortage. In training grants, the request of $^,2^0,000, 
will provide assistance to 101 schools of medicine, osteopathy, 
and public health for undergraduate training; 73 grants for post- 
graduate research and clinical training, including 395 traineeships ; 
and some specialized postgraduate training and basic sciences training. 



- 2 - 

Grants-in-aid to the States are requested in the amount of 
$2,125,000; and technical assistance to States in the amount of 
$560,000. This will allow for continuing the development of 
community heart programs, in which there have been noteworthy- 
developments in the majority of States, aided in large measure "by 
the technical assistance services of Public Health Service specialists 
requested by the States. 

For the research conducted by the Institute, the request of 
$6,376,000 holds essentially to the 1958 level of operation. This 
work, a keystone in the total national heart research endeavor, will 
devote its major effort in 1959 "to atherosclerosis, the greatest 
single problem in heart disease. . 

Heart disease continues as the leading cause of death, 
accounting for 5^ percent of all deaths. Heart disease mortality 
in 1956 was about Qk3 f kl0, and preliminary information indicates that 
in 1957 this total will be substantially higher owing to cardiovas- 
cular deaths related to the influenza epidemic. 

Progress is reported against the chief types of heart disease,. 
Against atherosclerosis in 1957; perhaps the most interesting develop- 
ments wore those concerned with lowering blood cholesterol as a 
possible means of controlling the disease; meanwhile basic studies 
added many new scientific facts not hitherto known. Advances against 
high blood pressure were also made, with new drugs for its control a 
feature of the year 9 Cerebral vascular disease was the subject of 
increasing attention, with interest focused both upon research and 



r i— . - 1 1 'Vf, 



- 3 - 
upon rehabilitation of stroke victims. Rheumatic fever and rheu- 
matic heart disease programs continued and were strengthened; adding 
to the control possibilities here was promising development of a 
new test for diagnosing the strep infections that precede rheumatic 
fever; if evaluations support preliminary findings, the near elimi- 
nation of the disease could he possible. Further surgical advances 
were made against congenital heart disease, making practical benefits 
available to thousands of patients. 

Research in aging received considerable support through the 
Institute's programs. The Center for Aging Research, located in the 
Institute, provided stimulus and coordination for gerontological 
research and its support by all the Institutes. Noteworthy here 
during the year was the initiation of the first grant -supported, 
comprehensive, university-centered aging research program. 



OPENING STATEMENT 
hy 
Director, National Heart Institute, Public Health Service 
COMMITTEE ON APPROPRIATIONS 
1959 ESTIMATE 
for 
"National Heart Institute, Public Health Service" 

Mr. Chairman and Members of the Committee: 

This statement will review for the Committee progress in 
heart research and related activities and point out some areas 
which hold special promise for the future. During the present 
fiscal year, basic laboratory and clinical research has been 
strengthened both in the Institute's laboratories and in those of 
institutions receiving grants. Training programs have been enlarged 
to increase the supply of much-needed scientific manpower. Activi- 
ties designed to assist in the application of rapidly developing 
knowledge from research have progressed. 

Areas of heart disease in which the Congress has expressed 
particular interest have been the subject of intensive and extensive 
attack through the Institute's program, Among these is the field 
of high blood pressure, where there is being initiated a broad~scale 
study to evaluate drugs and to carry on related clinical investi- 
gations, and where the essential search for fundamental knowledge 



- 2 - 

continues. Another area receiving research emphasis is the aging 
process., with the Center for Aging Research, established last 
year, providing a new focus for coordinated effort, Progress has 
been made in epidemiology and georgraphic pathology— the study of 
factors indicating how, when, where, why, and whom heart disease 
strikes. Intensive efforts have been made along the important 
frontiers of knowledge concerning hardening of the arteries — the 
most important and most complex heart problem, yet one where new 
clues and leads are being turned up constantly. 

1959 RE QUEST COMPARED TO 1958 

These are among the activities of the National Heart Institute 
which the current fiscal year's budget of $35*936,000 has 
made possible. The request for funds for Fiscal Year 1959 is for 
the same amount: $35*936,000. This will permit the consolidation 
of gains of the past year and maintain important activities in 
cardiovascular disease research, training and in the application of 
new knowledge. The 1959 request will provide for research project 
grants at the same dollar level as this year $19,36^,000. In 1959 
awards will be made in support of approximately 1^227 research 
studies. 

Under the 1959 request of $1,375*000, U2o research fellow- 
ships awards will help alleviate the continuing scientific manpower 
shortage. 



- 3 - 

In the field of training grants, the Institute request of 
$1+,2*K),000 will provide aid to institutions and individuals for 
undergraduate and postgraduate training in order to increase the 
numbers of trained research scientists, teachers and highly skilled 
physicians in cardiovascular fields. The sum requested will provide 
assistance to 101 schools of medicine, osteopathy, and public health 
for undergraduate training; it will provide for 73 grants for post- 
graduate research and clinical training, including 395 traineeships. 
In addition, the sum will provide for some specialized postgraduate 
training and for grants for training in heart epidemiology and 
biometry, fields of especially short supply in trained manpower today. 

Another important Institute activity is aimed toward the 
reduction of illness and death from heart disease by the application 
of available control methods and the testing and development of 
newer ones Support for this program of aid to the States through 
grants is requested in the amount provided last year, $2,125,000; 
this will allow for continuing the development of community public 
health programs « This year there have been noteworthy developments 
in at least 39 States as a result of the State heart grants * A 
necessary complement to this program is the furnishing of pro- 
fessional and technical assistance, requested for 1959 in "the amount 
of $560,000, slightly les6 than the current fiscal year's amount. 
The essentiality of this service to the States from the Public 
Health Service staff of specialists is shown by their extensive 
use by the States and by new programs developed with their technical 
advice and assistance. 



- k - 

INSTITUTE RESEARCH 

The 1959 budget request of $6.^ million for the research 
conducted directly by the National Heart Institute itself holds 
substantially to the 1958 level of operations. This work, princi- 
pally '.. conducted at Bethesda, Maryland, represents a keystone of 
inter-related laboratory and clinical investigation of significance 
in the total national research endeavor against heart disease. It 
is continuing to seek and add to basic knowledge of fundamental 
physiologic and biochemical processes, since fuller understanding 
of these must precede the development of better methods to prevent 
disability and death from heart and blood vessel diseases. At the 
same time, more immediately practical therapeutic approaches con- 
tinue to receive emphasis, as, for example, in the development of 
new devices for replacing surgically damaged heart valves and 
vessels and in the design of antiarrhthymicj blood pressure -lowering, .: 
and diuretic drugs. 

However, the major effort in the Institute's research program 
is being devoted to furthering knowledge of atherosclerosis, the 
most serious form of hardening of the arteries. Atherosclerosis 
underlies coronary heart disease and "heart attacks" and is the 
greatest single problem in heart disease. Intensive studies are 
seeking more knowledge of the handling of fats by the body as the 
best single lead toward an understanding of atherosclerosis and its 
prevention. Promising new tools are currently being brought to 



y':tV\-< "" 



- 5 - 
bear on the study of the chemistry and metabolism of fats, and 
this will facilitate investigation of the role of dietary fats in 
the development of atherosclerosis. The funds requested for 1959 
will permit the sustaining of this and other essential work underway 
in the Institute's research program at about the same dollar level 
as in fiscal 1958* with carefully planned shifts of emphasis to take 
advantage of new clues as they develop from current research. 

Some trends of the heart program have been shown in terms 
of their relationship to the budget and to particular program 
activities. A few statistics will demonstrate the current status 
of the medical problem being attacked- -heart and blood vessel deaths, 
the leading cause of death in the U.S» 

PRESENT STATUS OF HEART DISEASE 

Mortality from cardiovascular disease in 195& was about 
8^3,^10 deaths --5^ percent of all deaths. Because of the influenza 
epidemic, an estimate of 1957 mortality cannot be made at this time. 
Preliminary information, however, indicates that, as in previous 
epidemics of respiratory illness, deaths from cardiovascular disease 
will be substantially higher in 1957 than in 1956. 

The gravity of the medical problems that constitute heart 
disease is indicated by a breakdown by type of the deaths it caused 
during 1956. Heading the list is arteriosclerotic heart disease, 
which includes coronary disease or "heart attack" victims --1+28,800 



- 6 - 
deaths. In second place is cerebrovascular lesions (brain blood 
vessel diseases and "strokes") — 179>HO deaths. Third is hyper- 
tension, with or without accompanying heart disease--^, J+60 deaths. 
In fourth position is nonrheumatic chronic endocarditis and other 
myocardial degeneration- -62, 110 deaths. General arteriosclerosis 
is fifth- -32, 1+20 deaths, followed by rheumatic heart disease and 
rheumatic fever--20,030. Various other diseases of the heart and 
circulatory system accounted for 36,1+80 deaths. Not included in the 
total were approximately 10,000 deaths from congenital malformations 
of the circulatory system and 2,800 from syphilitic aneurysm of the 
aorta. Thus, the enigmas presented by heart disease are complex 
and the solutions difficult. 

However, tangible progress has been made in the understanding 
of each of the major diseases of the heart and circulation during 
the past year. Some of these accomplishments and developments in 
the program of the Heart Institute during the current fiscal year 
follow. These developments are presented to a large extent in terms 
of their relationship to the types of heart disease mentioned above. 

INSTITUTE PROGRAM AS A WHOLE 

First, though, it should be said that the progress reported 
in these brief summaries represents work of the Institute, both 
through its grants and its direct operations, as an inter-related 
whole. For example, in the field of atherosclerosis, laboratory 
as well as certain clinical investigations receive the major attention 
of the Institute's own research. The largest part of our research 



- 7 - 
project grants are for studies in this field. Much of the acti- 
vity of the heart disease control program of grants and technical 
assistance to States is occupied with advising the States of the 
latest status of and advances in knowledge of atherosclerosis. 
Through public and professional information activities the Insti- 
tute collects and disseminates useful health information. 

This kind of many- faceted program involves many skills and 
disciplines, ranging from physiology, anatomy, epidemiology, bio- 
metry, biochemistry to the clinical and public health sciences. It 
involves many types of programs and many organisations, both public 
and private. It is encouraging to note that, in the past year, 
there has been a very real growth of cooperative interest and 
action on the part of many such organizations, including industrial 
and commerical groups, in the field of atherosclerosis. 

Conferences between Institute researchers, other government 
researchers, university and medical school scientists, and those 
from private firms and research centers have helped define problems 
and find ways to solve them. 

For instance, better and more precise methods have been badly 
needed for analyzing lipids (such as fatty acids). Present methods 
for separating and measuring and studying lipids do not permit full 
understanding of the important aspects of fats and atherosclerosis. 
Through cooperative conferences and working sessions with industrial 
and agricultural researchers who are experts in lipids and their 
metabolism, new information has been gathered which will be of great 
benefit to scientists studying atherosclerosis. 



QS..U 



- 8 - 
PROGRESS AGAINST ATHEROS CLEROSIS 

Perhaps the most interesting recent progress against this dis- 
ease lies in the great concentration of attention on ways to lover the 
"blood cholesterol content of the blood. There is now known to he a 
definite, although imperfect, correlation "between atherosclerosis and 
the "blood cholesterol. But it has also been definitely established 
that neither the fat nor the cholesterol in the diet is solely respon- 
sible. There is probably no one cause of atherosclerosis. However, 
for purposes of control, the fat in the human diet is more important 
than cholesterol. 

All other things being constant, the cholesterol level of the 
blood does not change with the simple addition of cholesterol in the 
diet. Addition of sufficient amount of a saturated fat, generally one 
that is solidified at room temperature, however, causes a rise in the 
cholesterol level. Addition of a sufficient amount of an unsaturated 
fat, generally one that is liquid at room temperature, results in a 
lowering of the amount of cholesterol in the blood. 

Studies are now underway exploring the effect of adding unsatu- 
rated fat to otherwise normal diets. Evidence to date indicates it 
would take a rather large additional intake of unsaturated fat to get 
the desired lowering effect, and it is not yet known whether this effect 
is accompanied by any prevention or control of atherosclerosis. To 
aid in public understanding of this, during the year a new booklet 



1 IS* 



- 9 - 
for the public, "The Food You Eat and Heart Disease", was issued, 
containing facts about today's knowledge of diet and its relation to 
atherosclerosis as well as other types of heart disease. 

Meanwhile, although the mechanism of the lowering effect of 
unsaturated fats on cholesterol is not yet understood, it has been 
found that it is not accomplished by slowing down the synthesis of 
cholesterol by the body« In addition, considerable insight has been 
gained into the mechanism by which fats are transported in the body, 
as well as into the relationship between protein levels and unesterified 
fatty acids. From still other findings it is heavily inferred that 
there is some damage to the blood vessel itself before cholesterol 
plays its role of facilitating the deposit of fatty materials in the 
vessel walls— and this, too, is the subject of further investigations, 
since the cause and mechanism of such damage are as yet unknown. It 
has been observed, however, that sclerotic deposits are found with 
greater frequency in areas where blood vessels are subject to greatest 
pressure. Another finding is that people with high blood pressure 
have more advanced atherosclerosis at a given age than persons with 
normal blood pressure. 

These and other findings by the hundreds of researchers engaged 
in this field are increasing the body of knowledge rapidly. Although 
many of the pieces do not fit into patterns today, and most of this 
knowledge is not yet sufficiently explored: for wide application, It 



- 10 - 
is encouraging that such a large volume of new data is being gathered. 
Much of it is from fundamental explorations of normal basic processes 
and is essential to ultimate understanding of the disease. 

On the more clinical side, studies are being conducted on such 
questions as the effects of heparin, an anticoagulant, in treatment 
of coronary artery disease; and a search is being made for any effective, 
nontoxic drug with which to inhibit the synthesis of cholesterol by 
the body. Many studies are underway adding information on diets and 
cholesterol in humans as well as in experimental animals. Surgical 
repair of diseased blood vessels, although not removing the cause of 
or curing atherosclerosis, has also progressed with new operative 
techniques and devices. 

In brief, while the causes of atherosclerosis are not yet fully 
known and while predictive diagnostic measures, cures, or preventives 
are not now available, many complex factors are being delineated bit 
by bit, and 1957 has been a year of progress because of the acquisition 
of many scientific facts heretofore unknown. 

HIGH BLOOD PRESSURE 

In the field of high blood pressure, the year has also been 
marked by the uncovering of facts by basic research, but here more 
than in hardening of the arteries there have been advances in treatment. 
New drugs and combinations of new and existing drugs have been added 
for the physician's use in relieving patients suffering from high blood 
pressure, and at the same time understanding of how best to use these 



- 11 - 

drugs and of their mode of action has begun to be accumulated. Much 
remains to be done here, however, through research, and in this area 
both the research conducted and that supported by the Institute has 
been substantially concentrated. Included among these is a large- 
scale clinical cooperative study of antihypertensive drug therapy, 
supported by a Heart Institute grant and involving a number of hospitals, 
This study, which is just being set up, will provide useful information 
on the values and limitations of new drugs for the treatment of hyper- 
tension. 

New impetus was also given to hypertension research this year 
by the synthesis of a compound which appears to be identical with the 
natural blood pressure -raising substance found in the blood in some 
forms of high blood pressure. The possibility of preparing this 
vasopressor substance, angiotonin, in quantity may permit intensive 
study of the mechanism of arterial hypertension and of competitive 
drugs which, by blocking the action of natural angiotonin, may reduce 
high blood pressure of renal (kidney) origin. 

Control of hypertension by drugs that are both powerful and 
safe has made further advances. Chlorothiazide, a potent diuretic 
introduced for the treatment of edema in congestive heart failure, 
was found to possess unexpected hypotensive properties by two research 
groups. The action of chlorothiazide appears to be unique in that it 
has a direct blood pressure lowering effect, potentiates other hypo- 
tensive measures, and by its diuretic action improves the failing 



.-.ftOU CfV/.H tu-.-o 



■<>.!■ 



- 12 - 

heart and edema which complicate hypertension, Also, another drug, 
tetrahydrozoline, has "been found effective in lowering blood pressure 
after oral administration. 

Though the causes of essential hypertension remain unknown, the 
past year has produced clues to the possible basic biochemical mechanism 
producing the disease. The clues have come from studies of the chemistry 
of the brain centers which control blood pressure and other automatic 
body functions. The opposing stimulating and moderating mechanisms on 
the autonomic nervous system are mediated by centers believed to be 
under the control of chemical substances, known respectively as ser- 
otonin and norepinephrine. Substances which cause the release or 
prevent the action of these two chemicals have marked effects on the 
blood pressure, and it is possible that disturbances in the balance 
between these two types of centers may be responsible for the occurrence 
of hypertension. 

New chemical compounds with the ability to block the metabolic 
pathways of both serotonin and norepinephrine have been discovered 
and are undergoing intensive study both as to their usefulness in 
elucidating the nature of the disturbance responsible for hypertension 
and for their therapeutic use in its treatment. 

Recent reports that these blocking drugs are highly effective 
in the treatment of angina pectoris have caused the initiation of 
attempts to confirm this interesting and, possibly, highly important 
observation. 



- 13 - 

A complex system of interacting chemical substances has "been 
found to be present in increased amounts in the blood of patients 
with hypertension. The system is identified by its ability to affect 
the contraction of the isolated frog heart and this preparation is 
used to evaluate the concentration of the various components and to 
follow their isolation. Studies aimed at isolating and identifying 
the components of this system are continuing as an essential pre- 
liminary to full evaluation of their significance. 

A substance found in normal human urine has been found to be 
a powerful dilator of blood vessels. Studies of the isolation of this 
substance are in progress in parallel with efforts to evaluate its 
possible significance in the regulation of blood pressure. Its 
concentration has been found to be markedly reduced in patients with 
low blood pressure. Examination of its variation from normal in 
patients with essential hypertension is in its preliminary stages. 

CEREBRAL VASCULAR DISEASE 

Disease of the blood vessels of the brain, which includes 
strokes, accounts for some 180,000 deaths each year, and some 2,000,000 
persons are estimated to be incapacitated. Much of the research of 
the National Heart Institute is of significance to this disease because 
hardening of the arteries and high blood pressure are the greatest 
underlying causes. This field, of course, is also of strong interest 
to sister Institutes, in particular the National Institute of Neurological 
Diseases and Blindness, which has mounted a strong program of research 



- Ik - 

in cerebral va&cular disease. Correlating endeavors, the two Institutes 
have during the year supported several scientific conferences which 
have resulted in the interchange of latest knowledge, in the defining 
of research directions, and in institution of new research enterprises. 

VThile prevention and cure for the majority of strokes await dis- 
coveries from research, much can be done to help the majority of 
victims. Many of the 2,000,000 incapacitated can be rehabilitated, 
and a large study has shown that perhaps 90 percent of stroke victims 
can be taught to walk again- -and 30 percent to do useful work. 
Rehabilitation to some degree of most stroke patients can, furthermore, 
be accomplished by the family and the family physician. 

The Institute through its Heart Disease Control Program in the 
Bureau of State Services has this year worked to stimulate and assist 
programs throughout the country seeking to create a more positive 
attitude about cerebral vascular diseases and to provide services 
helpful to the physician and his co-workers (such as nurses, therapists, 
and social workers) in helping stroke patients. Both the technical 
assistance function and the provision of grants-in-aid to the States 
are mechanisms which permit such productive activities. In this field 
as in others, such as rheumatic fever and congenital heart disease, 
these mechanisms aid worthwhile services like diagnostic clinics, 
training for health department personnel, physicians, and other medical 
personnel, and increasing the knowledge of the public. 



- 15 - 

Recognizing the need for public information on cerebral vas- 
cular disease, the Institute last year began preparation of a booklet 
on the subject, titled, "Cerebral Vascular Disease and Strokes". It 
describes and illustrates the nature of the disease and tells what 
can be done to help stroke patients. For the first three months after 
issuance early in the fall, requests from physicians, health department 
workers, hospital personnel, and the public have come in for an average 
of some 6,000 booklets per week; material and illustrations from it 
have been used widely by the press, major national magazines, radio, 
and television. Supplementary educational materials for health workers 
are planned on the subject of cerebral vascular disease in further 
support of State programs in the rehabilitation of stroke patients. 
RHEUMATIC FEVER AM) RHEUMATIC HEART DISEASE 

In this field, there has been real progress in the application 
of knowledge. Programs for the prevention of heart disease resulting 
from rheumatic fever are well established in many states and this year 
some fourteen states began new programs or expanded their prevention 
programs. By this means, thousands of children have now been diagnosed 
and treated for rheumatic fever and are being followed up to assure 
their continuing prophylactic treatment against recurrent attacks, one 
of rheumatic fever's chief dangers and one which can lead to heart 
valve damage. For those whose hearts have been already damaged, new 
surgical operations and improvement of older ones were developed from 
research. Diagnostic services aided by heart control grants and 



- 16 - 
techanical assistance provided through the states permitted the diag- 
nosis of heart valve damage, and thousands of repair operations were 
done throughout the country with a high degree of success. Illus- 
trating the effectiveness of the control work in rheumatic fever is 
the example of one city-wide program: nearly 2,000 new cases of 
rheumatic heart disease were found, stimulating the State's legislature 
to appropriate $150,000 for the program. 

Application of known measures appears to be accelerating the 
decline of rheumatic fever and rheumatic heart disease, hut present 
measures are far from ideal and present knowledge concerning this 
disease is incomplete. Research continues to seek full facts of its 
causes and to develop better methods for its control. 

In this latter area, a most promising development has occurred 
during the year aided by the operational research services of the 
heart control program. Today effective prophylaxis can prevent 
secondary attacks of rheumatic fever. But prevention of initial 
attacks, which almost always are preceded by a streptococcal or 
"strep" infection, has been very difficult. The antibiotics can 
eradicate strep. But there exists no quick, sure means for the 
physician to identify streptococci in "sore throats" and other 
illnesses. A quick, sure test for strep infections would mean that 
doctors could institute antibiotic treatment, eradicate the strepococci, 
and prevent rheumatic fever from making its first attack. A method 
developed by the Communicable Disease Center laboratory for rapidly, 



'hi 



% !' ;■ 'rt">f'.' 



■ \'- 'J 



- 17 - 
effectively detecting the presence of strep bacterium is "being given 
preliminary tests through the heart control program's operational 
research assistance designed for just such purposes. This test makes 
use of a fluorescent antibody that tags strep bacteria so that their 
presence can be detected on a slide smeared directly from a throat 
swab from the suspected case. If evaluations support preliminary 
findings, the near elimination of rheumatic fever and rheumatic heart 
disease would be within the realm of possibility. 

CONGENITAL HEART DISEASE 

The advances of surgery to save and help persons with valves 
damaged from rheumatic fever and with some arteriosclerotic difficulties 
have been mentioned. But it is in the field of congenital heart 
defects that perhaps the most dramatic surgical gains of the year 
have been made. By their nature congenital abnormalities can be 
treated only by surgical repair, and then only when diagnostic and 
operative techniques, which may be applied to the specific type of 
defect, have been developed. 

Congenital heart disease is no small problem, because many 
thousands today have heart or blood vessel defects they were born 
with--and other thousands are born each year. As basic and clinical 
research conducted and supported by the Institute seeks the causes of 
such congenital defects and means of preventing them, new and better 
diagnostic and surgical methods have also come from research to aid 
those who already have the condition and who can be given longer, 



- 18 - 
fuller lives through surgery. Among the notable advance has "been the 
development of the precise technic for locating the sight of abnormal 
openings between heart chambers; improved methods for measuring the 
effectiveness of the repair of a heart valve while the patient is still 
in the operating room; and improved technics of surgery using artificial 
heart- lung machines. 

The number of diagnostic tests of congenital heart cases made 
throughout the country today are in the many thousands. From these, 
patients are selected as needing or not needing surgery. The suc- 
cessful operations for congenital heart defects in the past year number 
in the thousands. So it can be said that while research and its 
application continue to be needed in this field, and will be strongly 
supported by the Institute program, the progress made and the human 
economic benefits derived in the past year have been considerable. 

BESEARCH IN AGING 

Because heart and blood vessel diseases have definite asso- 
ciations with age, gerontological research is an important part of 
the Institute's program. Several hundred research projects, directly 
or indirectly related to aging, were supported this year, and it is 
expected that even more research support will be concentrated in this 
area with 1959 funds. Through its cwn research, too, the Institute 
sustains one of the most comprehensive aging research programs in 
the country. 



- 19 - 

Additionally, the Center for Aging Research, established in 
late 1956 and administratively located in the Institute, serves to 
stimulate and coordinate research and training in gerontology "both 
through the grants and the direct research in this field by all of 
the Institutes. A number of integrated aging research studies are 
underway at Bethesda involving the combined efforts of scientists 
of several of the Institutes; in addition, the National Heart Institute, 
National Institute of Mental Health, and others carry on separate 
studies, with frequent and regular interchange of information. 

During its initial year the Center for Aging Research has 
been concerned with program planning, contacts with leaders in the 
field of gerontology, and participation in meetings and conferences. 
In addition to assisting development of the aging program within the 
Department, the Center has cooperated closely with the Gerontological 
Society in a survey to delineate research needs. 

Because of aging's complex nature, the key to the study of 
aging is the mobilization of a broad spectrum of professional skills, 
available only in modern institutions of higher learning. Moreover, 
the cohesive forces of a university itself, its primary function of 
teaching, its community of scholarship, all together provide an ideal 
environment for such a mobilization of scientific effort. These 
considerations have justified an experiment. In planning for 
augmentation of the National Institutes of Health effort in the 
field of aging, it was decided to assist in the establishment of 



- 20 - 

several large research centers operated by universities — should 
propitious circumstances arise to permit this. During early 1957 the 
Center for Aging Research worked closely with investigators at Duke 
University in developing plans for the first such university- centered 
activity. As a result, a research program dedicated to a multi- 
disciplinary study of gerontology was established at that University 
on September 1, 1957> to be partially supported by a grant of just 
over $300,000 a year for five years. The Heart and Mental Health 
Institutes arc sharing equally in this grant* The Center is now 
working with several other university groups interested in develop- 
ing similar large research programs. 

The Center for Aging Research, in cooperation with the Atomic 
Energy Commission, has developed a plan for a series of conferences 
on the similarities and differences between physiologic aging and 
radiologic life shortening. The purpose of these conferences, to 
be held in 1958 by the American Institute of Biological Sciences, is 
to bring presently known information to bear on this question in order 
that the general problem of senescence may be more effectively elu- 
cidated. The conferences may result in a publication that will 
establish a current base line of knowledge in this area. 

EPIDEMIOLOGY 

This field has received a great deal of attention in all phases 
of the Institute program, both in direct operations and in grants. 



- 21 - 

Already much information of value is being uncovered, and further 
knowledge from epidemiological studies will undoubtedly help to 
clarify many of the presently puzzling host of factors known to be 
associated with heart disease. A brief description of only a few 
of the many endeavors underway and some of their findings will serve 
to illustrate this field of work. 

In the long-term study carried on by the Institute at Framingham, 
Massachusetts, a randomly- selected cross-section of the adult popu- 
lation, who volunteered to participate, is being studied in detail 
to find out and analyse factors associated with the development of 
heart disease. 

A finding of interest has been recently reported. "Silent 
coronaries" — heart attacks that generally go unrecognized- -accounted 
for one- fourth of the coronary attacks that occurred in the study popu- 
lation in the first four years of the study. No significant differences 
of age, occupation, weight, blood pressure, or heart size were found 
to distinguish those who had "silent coronaries" from others who had 
more typical attacks. The heart damage was usually in a different 
location, however, and angina pectoris or heart pain did not result 
as often from the silent type. 

More information upon this and other facets of the development 
of heart disease, such as nutritional relationships, will be forth- 
coming from this continuing study. 



,'T uic!« to 



- 22 - 

Through the grants program, steps have been taken to bring 
together pathologists from several countries to clarify interpre- 
tations of data and to provide a better basis for studies of geo- 
graphic pathology of atherosclerosis. In addition, comparative 
studies are being supported to learn the pathological changes taking 
place in the human aorta (the great trunk; artery leading from the 
heart) under different racial, cultural and environmental conditions 
in different countries. 

Epidemiological studies of the incidence, prevalence, and 
factors involved in coronary heart disease and cerebral vascular 
disease are also receiving major attention through the technical 
assistance and grants to States program. These studies are conducted 
cooperatively with State and local health departments, heart asso- 
ciations, medical societies, and others. 

One such study in a six county area of North Dakota, executed 
primarily to develop procedures for community investigations of 
coronary heart disease, has been partially completed. Preliminary 
data are being studied to learn what characteristics are present in 
persons who have experienced manifest coronary disease as contrasted 
with representative persons of the same age and sex from the general 
population of that area who do not have coronary disease. Following 
the pattern established in this study, Connecticut and New York are 
planning similar studies. Both of these states have a coronary death 



■q/v, 



? i 



- 23 - 
rate considerably higher than that of North Dakota. Comparison of 
the findings of their studies should reveal information on the degree 
of association of occupation, physical exercise, diet and, other 
factors related to this disease. 

A study to determine the effect of the differing dietary 
habits of Trappist and Benedictine monks upon blood lipids and 
incidence of coronary heart disease has been initiated in Georgia, 
and its results should also cast further light on coronary disease 
development. 

While not entirely epidemiological in nature, studies that 
will yield information of epidemiological importance were supported 
through grants this year involving cardiovascular effects and relation- 
ships of the Asian Flu. A special research grant program established 
by the Heart Council made possible the rapid initiation of heart 
studies in the first major area of the Asian flu epidemic in New 
Orleans and subsequently at a limited number of other medical centers 
in the country. Clinical and physiological effects of virus infection 
on the cardiovascular system as well as epidemiological studies have 
been possible. 

Epidemiologic studies are also in progress in cooperation with 
other State and local health departments to determine whether viruses 
other than German measles, particularly the virus of Asian influenza, 
cause congenital heart disease. The virus of German measles in 
expectant mothers is already known to be a causative factor in babies 
being born with malformations of the heart or blood vessels. If other 
viruses also are influential, or if they are not, the information 
derived from these studies will be of import and value. 



- 2k - 
SUMMARY 

During 1957,* further progress was made in the Institute's own 
research toward increasing basic and clinical knowledge of disease 
processes affecting the heart and circulation. Expanding research 
activities in universities and hospitals throughout the country also 
made many advances as a result of the Institute's comprehensive 
support of research through grants. Training programs contributed 
to an increase in both clinical and scientific manpower. Health 
department activities directed toward heart disease in conjunction 
with medical societies and heart associations continued to be 
stimulated and moved steadily forward in many states and communities. 

Conduct of the Heart Institute's program during the year has 
been governed, as in the past, by balanced consideration of pressing 
needs and long-term objectives, weighted so as to assure sound and 
progressive development. Special attention has been and will be 
given to those areas recommended by the Committee. 



SUMMARY OF OPENING STATEMENT 

by 

Chief Dental Officer, Public Health Service 

before 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"Dental Health Activities, Public Health Service" 

The present dental health activities programs of the Service in- 
clude: the support of research through grants to non-Federal institu- 
tions, increasing the supply of trained dental scientists and teachers 
by awarding training grants and fellowships, the direct research pro- 
gram of the Dental Institute, the development of dental resources, and 
furnishing consultant and technical assistance to State and local dental 
programs. 

Grant funds during the past year have provided a continuum of 
support to competent investigators, primarily in dental schools. These 
funds have also allowed for some expansion in terms of a more broadly 
based total program. Good progress is being made not only in devel- 
oping the dental research potential of the Nation, but the program is 
also favorably influencing the quality of dental education itself. 

The research fellowships program is providing the dental graduate 
and undergraduate with the opportunity to broaden his training through 
research experience in the basic sciences. Graduates of basic science 



- 2 - 
departments are also given an opportunity to prepare for careers in 
dental research. During the past two years, 15 research training 
centers have been established by training grants. These centers are 
specifically designed to train individuals as teachers and researchers. 

The program of research at Bethesda is concerned not only with 
the causes, control, and treatment of dental caries and periodontal 
disease, but also with a number of other diseases and malformations 
affecting the mouth and adjacent structures. These include cancer, 
cleft lip and palate, oral manifestations of systemic disease, and 
the influence of oral diseases on other organ systems of the body. 

Currently, greatest research emphasis is identified with studies 
in the field of human genetics being conducted on a tri-racial group 
in southern Maryland; studies of the incidence and significance of 
bacteremias following oral surgical procedures; electron microscopic 
studies of the minute structure of dental tissues and bone; studies 
on the nutritional aspects of oral disease; and studies of tooth decay 
and pyorrhea utilizing germ-free animal techniques. These studies 
involve the cooperative effort of individuals who are trained in 
various fields of basic science. 

The program operated by the Division of Dental Resources consists 
of three major parts, namely, (l) studies to evaluate present and 



- 3 - 
future dental manpower needs of the Nation, (2) studies on methods of 
training and efficient usage of auxiliary personnel, (3) studies on 
cost and methods of administration of prepayment plans for dental 
services. 

The goal of the program of the Division of Dental Public Health 
is to develop new methods of dental disease control and to encourage 
their adoption by State and local health departments. Consultant 
services are made available to States and communities through the 
Regional Offices. Technical assistance is made available to assist 
in initiation of new control procedures such as water fluoridation. 
Studies are in progress and will continue regarding effective methods 
of furnishing dental care to the chronically ill and the aged. 



OPENING STATEMENT 

by 

Chief Dental Officer, Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"Dental Health Activities, Public Health Service" 

Mr. Chairman and Members of the Committee: 

This statement relates to those activities of the Public Health 
Service concerned with the prevention, control and treatment of diseases 
and abnormal conditions of the oral cavity. The budget proposal before 
you requests an appropriation of $6,293>000 for these activities in 
fiscal year 1959* This compares with $6,302,000 currently available. 

The importance of good oral health to the individual embraces 
the idea of the relation of dental health to total health. This 
concept becomes clearer as dental research probes the problems of 
bacterial action, nutrition, abnormalities of growth and development, 
hereditary factors and other areas of investigation. The utilization 
of new control procedures, the development of resources for dental 
manpower, the study of problems of aging, and the training of auxiliary- 
dental personnel to permit a broader coverage of dental treatment are 
among the other important phases of dental health activities included 
in this budget request. 

Dental diseases are the most nearly universal of the afflictions 
which affect the health of mankind, and their chronic recurring nature 



!'•' :! 



- 2 - 
presents a continually changing problem to each individual throughout 
life. The attention which we devote to the treatment, cure and pre- 
vention of dental diseases must be consistent with our interest in 
all health problems. Dental research, the first and most important 
component of a total dental health program, is making substantial 
contributions to basic biologic science. This is evidenced by studies 
in chemistry, nutrition, bacteriology, physiology, and other areas of 
investigation related to oral diseases. 

In June 1958; the National Institute of Dental Research will 
come to its Tenth Anniversary. During the years since its creation 
by the Congress, efforts have been directed toward developing a broad 
program of basic research both in the laboratories at Bethesda, and 
in the dental schools and research centers throughout the country. 
The most outstanding accomplishment has been the establishment of the 
efficacy and safety of fluoridation of public drinking water supplies 
as a means of substantially reducing tooth decay. 

The recently expanded research and training grants programs of 
the Institute have been utilized quickly by the dental schools. In 
some cases their teaching and research staffs have been expanded and 
curricula arranged to permit the establishment of research training 
centers. These centers are designed to increase the number of persons 
with knowledge and appreciation of research and its role in dental 
education and dental health. 

A brief description of the dental health programs and plans for 
their continuation are included in the following pages. 



XI 



- 3 - 
Research Grants 

The most significant development in the research grants program 
during the past two years has been the marked increase in the number 
and a broadening of the type of research projects being supported. 
The number of research projects now supported is approximately 300, 
distributed among 82 institutions in 32 States and 3 foreign countries. 
Over 90 percent of the dental schools now have active research projects. 
The same high standard of research quality has been maintained by the 
Dental Council through a critical evaluation of applications and the 
awarding of grants for only the most promising projects. 

It seems clear that the increased opportunities which have been 
provided during the past two years will profoundly affect the course 
of research in dental schools, and also have a deep-seated effect on 
the quality of dental education. In addition to continuation of basic 
and clinical research, it was possible for the first time, through pro- 
gram grants, to give investigators increased stability by long-range 
support, and permit a broadening of scientific base. 

The presently available funds have been expended largely for 
the purpose of continuing, on a broader and firmer base, the support 
of those individuals who had received grants in prior years. In 
planning for future requirements, the Council has appointed ad hoc 
committees to study the research needs in such essential fields as 
periodontal disease, aging, radiation, and abnormalities of growth and 
development. Also for purposes of long-range planning, the Council is 
studying the means whereby basic research related to dental disease can 
be encouraged in science departments of non-dental academic institutions. 



- k - 

Research Fellowships 

The fellowship program in coordination with our graduate train- 
ing program is fundamental to the research grants program since it 
furnishes a continuous supply of well-trained research workers. 
Fellowships are designed to increase the number of younger individuals 
trained primarily in the basic sciences related to oral health. 

Generally speaking, a dentist is trained and graduated essen- 
tially as a clinician with practically no research training or expe- 
rience. The research fellowship program seeks to correct this 
situation in several ways: 1) By introducing the undergraduate 
dental student during his formative years to some research experience 
through the part-time fellowship program; 2) By furnishing postdoctoral 
support to recently graduated dentists who wish to obtain fundamental 
basic science training together with research experience; and 3) By 
supporting through the special research fellowship the more experienced 
individuals, especially mature clinicians, who desire additional train- 
ing in those basic sciences relating to their clinical interests. 

A recent evaluation of the fellowship program shows that 97 
percent of the total of former dental research fellows are currently 
engaged in research. Moreover, 6j percent of the total are teaching 
in dental, medical or graduate schools. 

Training Grants 

The training grant funds are providing continued support for 15 
research training centers. These centers are located in schools 



- 5 - 
geographically distributed throughout the Nation. They are designed 
to provide future teachers and researchers as faculty members of 
dental schools. Emphasis is being given to the training of clinicians 
in research methods and procedures. For purposes of improving dental 
education and increasing the overall dental research potential, this 
combination of the teacher and research worker is considered funda- 
mental. Approximately 50 trainees were appointed during the first 
year of this program. 

During the past two years, four new dental schools have been 
established. It is anticipated that, during the next few years, 
between five and ten more new schools will be established and the 
enrollment of those schools already in operation will be increased. 
This places a high premium on the number and quality of individuals 
who are now in training and can assume teaching or research positions 
in the dental schools of the future. 

RESEARCH AT BETHESDA 

As newer knowledge is made available in the various health 
fields and as awareness and recognition of the intimate relationship 
existing between oral and systemic disease increases, the scope of 
responsibility facing dental research becomes ever broadened. With 
relatively few investigators available to cope with the many problems 
demanding attention, the number of research activities engaged in by 
the Dental Institute staff is necessarily limited. However, in 
recognizing the charge of responsibility to serve the health needs 



d fcv 



- 6 - 
of the Nation by adding to our store of knowledge, a broad approach is 
essential. Wherever possible, the intramural research activities are 
being correlated with extramurally-supported projects in order to cover 
as broad a frontal attack as possible on the oral disease field. While 
at the present time major attention is being given to a few specific 
areas, there is, nevertheless, a continuing responsibility to support 
minor activities which might bear considerable fruit in the future and 
represent the major activities of the next several years. Program areas 
of major emphasis are mentioned below: 

Genetic Study 

Research activities in the field of human genetics have been 
emphasized during the past year. The special interest in this study 
by investigators in all seven Institutes of the NIH has resulted in 
a program of ever-increasing productivity. Due to this broadened 
scope of responsibility, a separate Section on Human Genetics was 
recently established in the Dental Institute. The activities of this 
Section demonstrate a type of program which is particularly productive, 
both from the standpoint of dental research accomplishments and also 
the value to studies of other Institutes, Based on studies of a tri- 
racial isolate group of some 5>000 persons residing in Southern Maryland, 
a number of accomplishments may be cited. 

To date, 8 distinct hereditary defects of enamel and dentin have 
been discovered. These have been classified and described clinically, 
histologically, and by X-ray. 



- 7 - 

An unusual and previously undescribed bone disease, characterized 
by peculiar thickenings (hyperostosis), has been described and studied 
clinically. Found in 5 members of one family, the first symptoms of 
the disease characteristically appear at about h to 5 years of age 
with swelling, always on the right side of the jaw, accompanied by a 
facial paralysis, and gradually involving both sides of the face. At 
about 6 to 9 years there appears a loss of hearing and eye abnormalities. 
Of particular interest is the fact that although all bones finally 
become affected, the usual laboratory tests for calcium, phosphate, 
etc., in the blood are within normal limits. These cases are of spe- 
cial interest to investigators in the Institute of Arthritis and 
Metabolic Diseases. 

Also under study at present are a number of cases presenting 
abnormalities of speech. Attributed to a variety of hereditary struc- 
tural deformities (tongue-tie, cleft palate, malocclusion, and mal- 
formed teeth) , these speech defects are being thoroughly studied by 
means of X-ray, models, and tape recordings in order to evaluate the 
therapeutic benefits of speech therapy and surgical correction. This 
phase of the study is being conducted in cooperation with the Speech 
Clinic of the University of Maryland. 

Other important aspects of the overall genetic study, pursued 
cooperatively with investigators in other Institutes, are being related 
to the description and categorization of numerous hereditary disease 



• '■' 1 



- 8 - 

entities, some of which may have interrelated causative factors. These 

include albinism, anemia, deafness, eye disturbances (glaucoma), and 

a variety of other defects involving the heart, kidney, liver, spleen, 

and thyroid. 

Study of Bacteremias Following Operative 
Procedures in the Mouth 

For many years, it has been recognized that infection of the blood 
stream (bacteremia) can follow various oral surgical procedures, such 
as tooth extraction and routine treatment for pyorrhea. However, 
considerable difference of opinion lias been expressed relative to the 
incidence of these occurrences, as well as procedures for prevention. 
Current studies being pursued by this Institute have been related pri- 
marily to establishing the true picture of incidence. Based on newly 
devised techniques of blood culturing, both from the standpoint of 
sample size and growth media, an incidence of 85 percent positive 
blood cultures has been discovered after dental surgery and periodontal 
treatment. This unusually high figure is based on a series of 67 cases to 
date. It is apparent from these observations that special treatment 
procedures must be instituted by the general practitioner in order to 
avoid such serious sequelae as heart lesions following routine dental 
procedures. 

Studies on the Minute Structure of Developing 
and Mature Dental Tissues and Bone 

Important findings related to the crystal structure of calcified 

tissues have been made possible by techniques of electron microsco-py 

and electron diffraction. Of major concern in this general field of 



- 9 - 
tissue study is the development of more efficient equipment. Of par- 
ticular importance in this regard has been the development by inves- 
tigators of a technique for the successful preparation of ultra-thin 
tissue sections ( .00001 mm) . 

Evidence accumulated to date provides information on the general 
size, shape, and orientation of crystallites comprising enamel and 
dentin of the teeth. These studies are also providing important in- 
formation on the several stages in the life history of cartilage cells 
and the ossification of the cartilage matrix. With the utilization 
of X-ray microscopy, data are becoming available on the distribution 
and character of the mineral component of both the teeth and bones as 
it is progressively laid down during development. These studies in 
this important program area will further our understanding of the 
mechanisms of calcification as well as clarify the process of tooth 
and bone development. 

Studies on the Nutritional Aspects of Oral Disease 

Current studies are providing important evidence that nutri- 
tional factors play an essential part in dental caries and periodontal 
disease. For example, the level and composition of protein, as well 
as the presence of many distinct chemical entities, are being shown 
to have a marked influence on tooth decay in experimental animals. It 
is becoming increasingly apparent that factors beyond those confined 
to the oral cavity may be extremely important. For example, a 
significant reduction in tooth decay in rats is brought about by 



- 10 - 

administering a protein (lysine) and other chemicals "by stomach tube 
rather than by incorporation into the food. These observations that 
chemicals can affect the incidence of dental caries without any direct 
action within the oral cavity, provides evidence that systemic metabolic 
factors can be influential in increasing as well as decreasing dental 
caries. 

Having established the efficacy and safety of fluoride for the 
control of dental caries, current emphasis is being placed on other 
promising methods which might ultimately serve to completely control 
this still widespread disease. One approach is through the addition 
of dicalcium phosphate to the dietary. Based on animal studies at 
the Dental Institute and at Malmo, Sweden, rather significant evidence 
has been assembled to indicate that this mineral compound can bring 
about a pronounced protective effect. A field study to evaluate this 
phenomenon is contemplated for the immediate future. 

Studies Utilizing Germ-Free Animals 

Other than the excellent exploratory work at the University of 
Notre Dame, relatively little use has been made of germ-free animals 
to study dental problems. One of the more important current changes 
in program emphasis will be studies utilizing these methods. 

There is a strong background of experience among the Institute's 
investigators dealing with the production of experimental caries in 
rats, both from a bacteriological as well as a nutritional standpoint. 
Initial experiments with germ-free animals will deal with attempts to 



OjfJ« 



- 11 - 

produce caries in germ-free rats by the introduction of selected strains 
of oral bacteria. As the work progresses, it will be possible to study, 
singly and in combination, many of the nutritional factors which are 
thought to influence the development of, or susceptibility to, caries. 

Periodontal disease (pyorrhea) is also known to occur in rats, 
guinea pigs and hamsters. Although investigators have not studied this 
problem in detail as yet, there is a considerable backlog of information 
accumulated in other studies which suggests that certain bacteria play 
a role. Which specific bacteria are the most important, however, is 
not known. 

Questions of this type cannot be satisfactorily resolved 
unless the extensive oral microflora of the animals can be controlled 
as is possible in germ-free work. 

Studies Presenting Promising Leads for Future Activities 

1. Histochemical procedures are being developed for the demon- 
stration and precise localization of enzyme activity adjacent to malig- 
nant growths. This holds promise of being a useful diagnostic tool. 
Other histochemical studies are showing, more clearly than before, 
enzyme activity in developing bones and teeth. These promise to add 
much to our knowledge of calcification. 

2. Studies on the chemical composition of saliva in caries-free 
and caries-active individuals, as well as a determination of the degree 
to which salivary composition may reflect general disease states, are 
providing another base upon which to evaluate the mechanisms of oral 
disease. 



- 12 - 

3>. Studies on the physiologic response of ambulatory patients 
to various general anesthetic agents are leading to a re-appraisal of 
certain concepts of systemic reactions to various types of anesthesia. 

k. Studies on prosthetic reconstruction for rnaxillo-facial 
defects and the formulation of principles of design that could con- 
tribute to improved functions of mastication and speech are prom- 
ising much needed help in these categories of disablement. 

5. Experimental studies of hereditary factors involved in the 
caries process ( e.g ., development of caries-susceptible and caries- 
resistant strains of hamsters) are providing worthwhile information 
or. caries etiology. 

During fiscal 1959* it is planned to continue the above men- 
tioned research studies. 

DENTAL PUBLIC HEALTH 

The goal of the programs operated by the Division of Dental 
Public Health is to develop and apply the findings of basic research 
for the prevention and control of dental diseases and disorders as 
widely as possible through public health procedures. Achievement of 
this objective requires public awareness and acceptance of good dental 
health practices as well as adequate resources and personnel. 

Although substantial advances in controlling and preventing 
some dental diseases have been made through discoveries of research 
and new techniques, the resources of States and communities to apply 
these measures are limited. At the State and local levels there is a 



;- iu 



- 13 - 
great need for trained personnel and funds to plan and develop dental 
health programs which would apply known preventive and control measures, 
and provide care for special population groups. These programs cannot 
adequately meet the present dental health problems, much less adapt to 
the changing dimensions of these problems resulting from an increasing 
shortage of dentists, the rising demand for dental services, and the 
increasing proportion of the population which is aged or chronically 
ill. Solutions to these problems can be approached realistically only 
through long-range dental programs at the State and local levels, and 
require adequate personnel and sound budgetary practices. 

Through qualified dental staffs in Public Health Service regional 
offices, the Division provides professional and technical assistance 
to the States and communities in such areas as personnel utilization, 
program planning and budget management, definition of dental health 
problems, administration of dental clinics, dental services for public 
assistance recipients, and in-service training programs. Dental hygiene 
and statistical consultant services are furnished to the States for 
special projects. Technical assistance on the fluoridation process 
and methods of maintaining fluoridation standards are made available. 
The Division also engages in studies to develop and improve materials 
and equipment and new preventive and control measures which might be 
adapted to State and community use. 

Fluoridation of public water supplies for the partial prevention 
of dental decay will continue to receive emphasis in implementing the 



- Ik - 

program activities of the Division. Currently more than 32.5 million 
people in over 1500 communities, including a majority of the Nation's 
18 largest cities, are now using fluoridated drinking water. Analysis 
of the status of fluoridation in this country indicates that greater 
effort must be made among the smaller communities. About 90 percent 
of all public water supplies are in communities with less than 5,000 
population. 

One problem associated with fluoridation has been a persistent 
shortage of materials suitable for use in fluoridating community water 
supplies. A few communities have had to stop fluoridation temporarily. 
Research efforts in the laboratories of this Division have been effective 
in developing a technique for using fluorspar, one of the most common 
substances on the earth's surface, for this purpose. Fluorspar is 
readily available and its use will reduce the cost of fluoridation by 
two-thirds. This technique is now being demonstrated in a small 
community and will be used in a larger community during the coming 
year. 

The practicability of a device developed by the Division for the 
fluoridation of individual water supplies now makes possible the exten- 
sion of the benefits of fluoridation to rural and suburban populations 
not served by public water supplies. Testing of this device has 
progressed to the point where its potential for successfully meeting 
the problems of rural fluoridation is assured. 



'"U 






- 15 - 

Studies of methods for removing excess amounts of naturally 
occurring fluorides from public water supplies have resulted in the 
development of practical procedures for this purpose which compare 
favorably in cost with other water treatment measures. Release of 
this information during the current year has produced considerable 
interest and it is planned to actively encourage and assist com- 
munities in defluoridating water supplies where dental fluorosis 
i6 a problem. 

During the past year substantial progress has been made in 
study of the special problems related to the provision of adequate 
dental care services to the institutionalized and homebound chronically 
ill and aged, Activities presently in operation were designed to 
accumulate data on the nature and extent of this problem, and to 
develop methods for providing dental services for these groups. 
Projects are currently being conducted at the Nevada State Mental 
Hospital, Reno, Nevada; the Montefiore Hospital and Beth Abraham 
Nursing Home, Bronx, New York. 

Prompted by the observation that the percent of voluntary 
participation of children in community care programs is lower than 
expected, several small-scale exploratory studies will be performed 
during the next 18 months to gain some insight into the reasons 
why treatment is refused. Such information would be of great value 
in developing measures or techniques which would promote greater 
acceptance of health procedures by the public. 



- 16 - 

Preliminary findings from a study conducted by this Division in 
Puerto Rico of adults with untreated cleft palate, indicate that facial 
development has not been impaired and the dental arches have developed 
normally. These findings indicate that efforts to obtain closure too 
early in life may often fall far short of their objective and sometimes 
produce malformed arches and extensive scar tissue. These circumstances 
seriously interfere later in life with attempts to provide the indi- 
vidual with prosthetic appliances. It would appear from the study 
that many cleft palate cases should not be surgically treated and 
that restoration of function should be accomplished through prosthetic 
devices. The number of cases examined, however, will need to be in- 
creased before conclusive evidence is obtained confirming the early 
findings. 

DENTAL RESOURCES 

One of the greates threats to the Nation's dental health is the 
growing shortage of dental manpower. The Division of Dental Resources, 
which is giving special attention to this problem, estimates that on 
the basis of demand alone the current shortage of dentists stands at 
13>500. Estimates prepared by the American Dental Association indicate 
that if the current dentist-population ratio is to be maintained, the 
number of dental graduates will have to be increased by approximately 
100 per year for the period 1960-1975. 

The current situation is primarily the product of a period of 
tremendous population growth with only a moderate increase in the 



• U' 



- 17 - 
supply of dentists. Since 19^0 only 10,000 practicing dentists have 
been added to serve a population increase of more than 1+0 million. 
Concurrently, there has been an increased standard of living, higher 
educational levels of the public, an increased use of bank plans for 
post-payment of dental care, and a trend toward greater urbanization, 
all of which are factors associated with increased demand for dental 
services. 

Prepaid dental care is expected to grow in the same dramatic 
fashion as prepaid medical and hospital care. However, it is generally 
agreed that because of the nature of dental disease and dental care, 
many of the principles which have governed the development of prepaid 
medical care are either inapplicable to dentistry or must be modified. 
Special and immediate preparation is required to assure that voluntary 
dental prepayment programs are established on a sound basis, that they 
grow in an orderly fashion, and that maximum benefit is derived by all 
concerned. 

The Public Health Service is being called upon to assist in 
solving the new set of problems associated with both the manpower 
shortage and prepayment in dentistry. Requests have been received 
from State health authorities, dental societies, labor-management 
groups and others . The Service has been able to respond only in a 
very limited fashion. 

Two studies on dental manpower needs were completed during the 
past fiscal year. The first was a study of dentist requirements 



- 18 - 

through E-ggTin l6 southern States, which was undertaken in cooperation 
with the Southern Regional Education Board. As in the case of the 
earlier western States study, the findings for the south will provide 
a basis for the regional and State planning which is needed if future 
demands for dental services in the region are to be met. 

The second study, just completed, was conducted in cooperation 
with the New England Board of Higher Education. The pattern of the 
study follows that used in the west and south. Findings will serve 
as a basis for regional and State planning to combat the dental man- 
power shortage in the New England area. 

Another facet of the problem of alleviating the dental manpower 
shortage is the training and effective use of auxiliary personnel 
(dental hygienists and dental assistants). During the past fiscal 
year a compilation and analysis of data pertaining to facilities for 
training dental hygienists, and the characteristics of dental hygienists, 
their distribution, nature of their employment and the plans of non- 
practicing hygienists to return to work was completed. The findings 
of the study will be used for appraising the current status of the 
hygienist's profession and for projecting estimates of future needs. 

A research and demonstration project, designed to teach dental 
students to use dental assistants effectively, is now in its second 
year of operation. Six dental schools are participating and each has 
completed at least one year of the program. Reports from the schools 
indicate that the objectives of this program are realistic and attainable. 



- 19 - 

A study of existing prepayment dental care plans was completed 
during the year. The report of this study includes a basic description 
of comprehensive and limited prepaid, as well as reduced fee, dental 
care plans sponsored by unions, employers, fraternal or community 
groups. Each plan is described as to sponsorship, area served, type 
of benefit, eligibility, number of enrollees, method of operation, 
benefits, and cost. Another important contribution in the field of 
dental prepayment was made with the completion of a study of the 
development and operation of a State-wide dental service corporation. 

A continuation of the regional studies of dental manpower require- 
ments is proposed which is expected to culminate in a nationwide report. 
The Division will assist individual States in studying local dental 
manpower problems and in planning for new or expanded facilities. 
Without some technical assistance, most States would be unable to 
undertake comprehensive surveys of this type. These activities are 
expected not only to provide the basic information essential to man- 
power planning but to help considerably in stimulating appropriate 
action by responsible State and local authorities. 

The Division has collected and plans to continue to obtain 
information on various aspects of dental prepayment. The areas in 
which the need for additional information is greatest include: (a) 
professional services required by different plans and different 
population groups; (b) the most reasonable actuarial methods to use; 



- 20 - 

(c) cost determinations of various types of programs; (d) statistical 
compilations of pre-existing and maintenance dental needs; (e) simple 
and inexpensive administrative techniques; and (f) greater knowledge 
of utilization patterns for accurate predictions of premium amounts. 

Currently under study are five different types of programs 
serving different types of population groups. Some of this needed in- 
formation will evolve from these studies in the future. 

The pilot studies initiated during fiscal years 1957 and 195^ 
in the dental schools of the Universities of Alabama, Illinois, Iowa, 
Minnesota, North Carolina, and Kansas City were designed to assist 
the schools in developing and assessing effective techniques for 
teaching dental students to work efficiently with chairside assistants. 
It is essential that this program, now in the second year of a five- 
year schedule, be continued and that it be expanded when possible. 
The use of chairside assistants has not been a part of the dental 
school curriculum, and the habit of working alone, acquired in school, 
carries over into practice and is not easily broken. Both the American 
Dental Association and the dental schools agree that the dental school 
curriculum should be altered to incorporate training in the use of 
chairside assistants, so that future graduates will, at the outset, 
acquire work habits which permit the fullest possible utilization of 
their scarce skills. 



- 21 - 

It is also proposed to continue the effort to perfect an index 
of malocclusion (disfiguring abnormalities of the teeth and jaws) . 
The development of a reliable measuring device for assessing the 
prevalence of malocclusion will permit epidemiological surveys in this 
field and may lead to the development of preventive measures. Immediate 
plans in this area include studies to test the usefulness of the 
present approach in determining the existence of age and sex-specific 
values, and in comparing the malocclusion picture in groups with high 
and low levels of dental care and periodontal disease. 



SUMMARY OF OPENING STATEMENT 

by 

Director, National Institute of Arthritis and Metabolic Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"Arthritis and Metabolic Disease Activities, Fublic Health Service" 

The 1959 budget proposal for Arthritis and Metabolic disease 
activities is $20,592,000. 

Our present research attack on diabetes, arthritis and other 
metabolic diseases may conveniently be considered in two parts : 
First, efforts to improve palliative or control measures; and 
second, fundamental biochemical and metabolic studies designed to 
furnish information on the cause of these disorders and to permit 
their eventual eradication through prevention and cure. A healthy 
balance between these two separate lines of attack is sought and, 
it Is believed, has been attained. 

In palliation, the notable developments of the past year 
include the extensive and fruitful evaluation of the therapeutic 
effectiveness of an oral drug against diabetes called tolbutamide 
or "Orinase"; the preliminary testing of additional compounds 
which lower blood sugar levels ; and the enlargement of the armamen- 
tarium against the rheumatic diseases through the clinical' trial 
of new steroids and other drugs, including antimalarial compounds. 



(' . ;• : -' 



- 2 - 

In basic research, knowledge of the metabolism of sugars 
and fats and of many additional important biological substances 
has been greatly extended. Noteworthy progress in understanding of 
nucleic acids, basic structural units related to the viruses and 
the genes, has been achieved. Further information on galactose 
diabetes, or galactosemia, a so-called "molecular" disease, has 
been obtained; and the underlying metabolic defects in two addi- 
tional molecular diseases --alcaptonuria and congenital non-hemolytic 
jaundice --have been discovered. 

ITew areas of emphasis in this Institute include physical 
biology, biochemical and biological studies with "germ-free" 
animals, and gastroenterology- -including ulcerative colitis, 
regional ileitis, and peptic ulcer «, 



OPENING STATEMENT 

Director, National Institute of Arthritis and Metabolic Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"Arthritis and Metabolic Disease Activities, Public Health Service" 

Mr Chairman, Members of the Committee: 

For fiscal year 1959> the budget request for the National 
Institute of Arthritis and Metabolic Diseases totals $20,59 2 ,000, 
an increase of $207,000 over the appropriation for fiscal year 
1958- This increase is to expand work in the field of physical 
biology through grants for research and training and through 
intramural research, The increased emphasis on this field of 
research represents a logical extension of program developments 
of recent years. 

Since the National Institute of Arthritis and Metabolic 
Diseases was created in 1950, its more important developments 
have been: 

(1) The initiation and expansion of a nationwide multi- 
disciplinary attack on the problems of diabetes; 

(2) the creation of a dynamic program of clinical and basic 
research and training in the rheumatic diseases; 

(3) the evolution of a rapidly moving and highly-rewarding 
assault on basic problems of metabolism through fundamental studies 
in biochemistry, endocrinology, and related disciplines; 



- 2 - 

(h) the initiation of basic and clinical studies and of 
training in gastroenterology; and 

(5) the expansion of a program in physical biology through 
grants for research and training and through small increases in 
intramural laboratory research. 

Each of these developments has been made possible, in whole 
or in part, by the interest and support of the Congress. In par- 
ticular, there has been provision of increased funds for diabetes 
research each year since 195 ! +» In fiscal year 1957 funds were 
appropriated specifically for work in endocrinology and related 
basic studies, and in fiscal year 1958 funds were similarly made 
available for gastroenterology and physical biology. 

Succeeding sections of this report will discuss in greater 
detail the program evolution in each of these areas, as well as 
the changes in emphasis which have been made in order to take ad- 
vantage of new concepts and new techniques. In addition, there 
will be presented a few of the many advances in knowledge result- 
ing from the appropriations of the Congress to this Institute. 

HISTORICAL: EVOLUTION OF THE INSTITUTE 
Established in 1950 under the provisions of Public Law 692, 
the National Institute of Arthritis and Metabolic Diseases received 
its first direct appropriation in 1952. For many years prior to 
1950, laboratories which now constitute a part of this Institute 
were concerned with basic studies in chemistry, pathology, 



- 3 - 

pharmacology, physiology, and nutrition. In 19^7 > they were 
grouped together into a division known as the Experimental Biology 
and Medicine Institute. These laboratories over the years of their 
existence have had an outstanding record of accomplishment in 
fundamental research. They have contributed important information 
on the structure of sugar molecules, developed new painkilling com- 
pounds, carried out some of the earliest work on the action of the 
sulfonamides, particularly against pneumococci, and made basic 
observations of the widespread deficiency disease pellagra, lead- 
ing to its virtual elimination as a health hazard in this country. 

New Research Areas . A trend toward the study of the 
functions and modes of action of cellular components as a means 
of understanding body processes in health and disease began some 
years ago with the creation of a unit to carry out research on 
enzymes. Since that time, the study of chemical reactions in cells 
and of the enzymes catalyzing these reactions — an extensive field 
known as intermediary metabolism — has attained greatly increased 
importance both at Bethesda and in the scientific world in general. 
The older chemistry laboratories of this Institute now have joined 
this trend and are shifting their major interest from the structure 
of carbohydrates and analgesics to the metabolism of various com- 
pounds in the body and to the chemical reactions of the products 
of metabolic change — the so-called metabolites. 






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In addition to the evolution of the non-clinical research 
laboratories, another major change has been "brought about by the 
opening of the Clinical Center. Problems having a direct bearing 
on clinical medicine have been undertaken, especially as they are 
related to diabetes, arthritis, and other diseases of connective 
tissue, diseases of the thyroid, pituitary, and other endocrine 
glands, disorders of the blood and blood-forming organs, and 
various other metabolic diseases, such as the familial diseases 
of childhood. 

One of the principal effects of the introduction of clini- 
cal investigation, aided by the expansion of intermediary metab- 
olism, has been to provide an opportunity for cross-fertilization 
of ideas between basic scientist and clinical investigator. Their 
close collaboration has already resulted in elucidation of the 
cause and development of means of alleviation of certain diseases 
of probable genetic origin--so-called molecular diseases. This 
will be discussed at greater length in another section of this 
report. 

Grants Programs Broadened . The extramural programs of this 
Institute, which include grants for research projects, research 
fellowships, and training grants have also experienced major 
changes since their inception. With the establishment of the 
Institute, a focal point was for the first time provided for a 
nationwide attack on a wide variety of disease entities, including 



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diabetes, arthritis and other rheumatic diseases, endocrine dis- 
orders, liver diseases, nutritional deficiencies, blood disorders, 
and other related ailments. The initial effort was directed in 
great measure towards stimulation of interest in the various 
arthritides. As increased funds permitted expansion into other 
areas of its responsibility, the Institute extended its support 
for research and training to diabetes and other metabolic diseases 
(subsequently, also, to gastroenterology and physical biology). 
From very small beginnings in 1950; these programs have grown to 
the point where they represent a vital and effective force in 
furthering the conquest of the diseases for which this Institute 
has categorical responsibility, 

RECENT TRENDS AND DEVELOPMENTS 

Physical Biology . During the past generation, the applica- 
tion of chemistry to biological and medical problems led to the 
development of a completely new approach, biochemistry, which has 
developed to a fine point and provided answers to many formerly 
insoluble problems. 

But many problems remain, and underlying many of these are 
physical forces which to date have been only superficially ex- 
plored with what are, apparently, inadequate techniques. 

There is general agreement that the application of the 
techniques of modern physics to medical and biological problems 
will provide the answers to what now appear to be insoluble 



-.6 - 

problems, and that the next generation will see results comparable 
to the great contributions of chemistry in the immediate past. 

Anticipating rapid and significant developments in this 
field of biophysics, the Institute, supported in this view by the 
Congress, has during the past year moved to expand and broaden its 
operations in this relatively new and fertile field of exploration, 
The techniques of the physicist are being increasingly brought to 
bear upon a growing number of natural phenomena. And, in con- 
junction with this development, the techniques and skills of the 
mathematician, too, are being tooled up for application. In the 
past the basic science of mathematics has not been fully utilized 
in solving biological problems. A section of mathematics now has 
been set up in the Institute and this section will provide leader- 
ship in the application of creative mathematical techniques to 
biological problems. 

In the development of the field of physical biology there 
has been progress not only at Bethesda, but throughout the nation 
as well, due in large part to Federal support. New studies of 
various aspects of physical biology have been undertaken under 
National Institute of Arthritis and Metabolic Diseases research 
grants Also, because of the lack of qualified investigators in 
this new field, particular emphasis is being placed on training. 

Gastroenterology . Increases in the 1958 budget made it 
possible to undertake support of a number of new research projects 
in various aspects of gastroenterology, with particular emphasis 



- 7 - 

on fundamental studies in physiology, biochemistry, and pathology 
as potentially the most fruitful approach to ultimate relief for 
the thousands suffering from such poorly understood afflictions 
as ulcerative colitis, peptic ulcer, and regional ileitis. Here, 
again, training has not been neglected. Funds provided by the 
Congress have made it possible to provide for the training of 
young clinicians, as well as advanced training for physicians, 
in gastroenterology a6 well as in the traditional areas of 
arthritis, diabetes, and other metabolic diseases. Development 
of additional skilled personnel in all of these areas, several 
of them too long neglected, is considered to be potentially most 
rewarding and of vital importance to future developments in these 
fields. 

Sound information concerning the prevalence of ulcerative 
colitis, regional ileitis, and peptic ulcer awaits extensive and 
detailed study, but it is estimated that ten percent of the world's 
population have, will have, or have had an active peptic ulcer. 
Physicians are just realizing that the commonest cause of rectal 
bleeding in children over two years of age is ulcerative colitis. 
Expenditures by the Institute in research and in training grants 
in gastroenterology studies increased by some $750,000 in 1958 
and this level will be continued within the 1959 budget before you. 
An encouraging advance in peptic ulcer research has been made dur- 
ing the past year: In basic physiological studies on the motility 



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- 8 - 

of the gastrointestinal tract and the production of pain, it has 
"been found that excess motility of the tract, in addition to the 
over-production of acid, is the important factor affecting the 
production of the ulcer and the subsequent pain. New drugs are 
"being developed and tested to reduce hypermotility and are prov- 
ing effective. 

Germ-Free Animals . Experimental animals may be born and 
reared in a "germ-free" state through the use of new techniques 
and very specialized equipment developed at the University of 
Notre Dame. The availability of such "germ-free" animals now is 
making possible investigations which heretofore could not be at- 
tempted, endeavors which may yield answers to riddles which have 
long remained unsolved. At the present time studies are in 
progress on the influence of intestinal bacteria on nutrition 
and on a variety of metabolic processes. 

DIABETES 

Diabetes is probably the best-known and most important of 
the metabolic diseases. The diabetic patient is unable to utilize 
sugar properly, either because of decreased production of insulin, 
the principal hormone of the pancreas, or because of interference 
with its action. 

Approximately 25,000 people die each year of diabetes while 
another 25,000 die of complications associated with the disease. 
About two million persons in the United States suffer from it. 



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- 9 - 
Diabetes has an iusidious onset, is hereditary in nature, and 
afflicts people of all ages. It cannot be cured. In the past 
it has been possible to control the high blood sugar moderately 
well in many patients with insulin injections, but this method of 
management is far from ideal. 

Research Attack . The Institute is at work in two principal 
directions to deal more effectively with diabetes. Efforts are 
being exerted toward obtaining smoother, better tolerated means of 
controlling the clinical disease, as exemplified by study of the 
oral drugs; and the search is being pushed for fundamental informa- 
tion on the disease process and on the action of insulin, in the 
belief that ultimate success in dealing with diabetes depends on 
detailed understanding of the basic body processes for making use 
of all vital food substances, not just sugars, and of how these 
processes are deranged in the diabetic patient. 

To accomplish this task, the grants program has been in- 
valuable and the growth of interest in this important field, as 
shown by awards for both research and training, has been most 
heartening. The intramural research program is carrying on in 
the laboratory many projects which are providing basic information 
concerning carbohydrate and fat metabolism and the structure and 
action of insulin and related hormones. This effort is aided 
greatly by the fact that the Scientific Director of the National 
Institute of Arthritis and Metabolic Diseases, Dr. DeWitt Stetten, Jr., 



- 10 - 

is one of the world's foremost carbohydrate and enzyme biochemists ; 
his outstanding work on glycogen, the principal storehouse compound 
of the body for sugar, for which he received the Banting Award of 
the American Diabetes Association, will be described. 

The clinical investigations program on diabetes in the 
Clinical Center has been proceeding on a modest scale. Relatively 
intense and careful study has been given to small groups of 
patients with special problems. Work has recently revealed the 
presence of substances which are antagonistic to insulin and its 
action in the blood of diabetic patients who represent difficult 
management problems. This past year a detailed study was completed 
which corrected a long-prevalent notion and indicated that the 
peripheral nerve complications of diabetes could not be laid to 
abnormal metabolism of the B vitamins. 

The Clinical Problem: Oral Drugs . The search for better 
means of controlling diabetes and its symptoms- is being pressed 
forward. Just two years ago it was reported that new drugs had 
been found which had potent blood-sugar-lowering action when taken 
by mouth. The first of these drugs, carbutamide (BZ-55) was soon 
found to be toxic and was withdrawn. The second, tolbutamide 
(Orinase) has appeared to be virtually non-toxic and is being 
widely used. 

Bitter experience in the past, however, with compounds 
which have seemed initially to be both safe and effective but 
have proven to be toxic and ultimately useless on long-term 



- 11 - 

observation, makes thorough investigation necessary. The Insti- 
tute is supporting clinical observations of the long-term effects 
of Orinase in numerous patients as well as laboratory studies of 
its toxicology and mode of action. 

It is important to determine whether Orinase possesses or 
in some way enhances certain of the key actions of insulin; if it 
does not, then the lowering of blood sugar by Orinase probably 
does not really help the diabetic to make proper use of essential 
food elements. In addition, questions concerning the possibility 
of damaging effects from long-term action of Orinase on various 
organs, such as the liver, and on hormone systems and enzymatic 
processes which regulate the metabolism of sugars, must be settled 
before it can be safely stated that Orinase is a significantly 
valuable compound for improving control over this important and 
widespread disease. 

During the past year investigators in the Institute have 
devised a technique of administering Orinase intravenously which 
is expected to be widely useful in helping to determine the 
mechanism of Orinase action and comparing it directly with that 
of insulin. Clinical studies using this new technique, supported 
^y in vitro tissue work, indicate that Orinase interferes in some 
way with the output of glucose by the liver and strongly suggest 
that Orinase does not act primarily by enhancing the peripheral 
action of endogenous insulin. 



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- 12 - 

Various research centers, supported in large part by 
Institute grants, are investigating other suggested actions 
of Orinase, including the inhibition of insulinase, the enzyme 
which inactivates insulin, and interference with the production 
or action of glucagon, a pancreatic hormone which favors the re- 
lease of glucose from its storage depots. Particular attention 
has been centered on the idea that Orinase stimulates the insulin- 
producing cells of the pancreatic islets, and findings of Institute 
grantees favor this concept. If this mechanism is the correct one 
and if long-continued stimulation of the pancreatic cells does no 
ultimate harm, then it would probably follow that Orinase or 
similar compounds might have a definite place in diabetes therapy. 
Much evidence contradicting this point of view has been presented, 
however. As a result, the conclusion at this time is that the 
mode of action of Orinase is not with certainty known and that 
it is not yet clear that diabetics are deriving actual physiologi- 
cal benefit from its use. 

In addition to the work on Orinase, Institute grantees are 
testing a newer oral hypoglycemic agent DBI, a compound thought 
to be effective in lowering the blood sugar in some patients who 
do not respond to Orinase, such as juvenile diabetics. Manifesta- 
tions of toxicity, or side effects, are said to occur in a rela- 
tively high proportion of patients. It is as yet much too early 
to evaluate the possible usefulness of this drug. 



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- 13 - 

Metabolic Problems: Basic Studies , Diabetes is a complex 
disorder which, although manifested by abnormal levels of glucose 
in the blood and by spillage of sugar in the urine, actually in- 
volves alterations in many metabolic processes. For this reason 
investigations must be pursued in many areas of metabolism in an 
effort to characterize precisely the various biochemical derange- 
ments in this disease. Since incomplete breakdown of fats occurs 
during certain phases of diabetes, the metabolism not only of 
sugars but also of fats must come under scrutiny. Studies are 
also concerned with the structure and function of insulin and, 
because of multiple interrelationships, the biochemistry and 
metabolism of other regulators, especially the hormones of the 
pituitary and adrenal glands, must be carefully investigated. A 
few examples of these basic studies will be cited. 

Sugar Metabolism , Sugar is stored in the body in the form 
of glycogen, principally in the liver and in the muscles. Recent 
studies at the Institute have revealed the remarkable suitability 
of glycogen for its sugar storage function by disclosing its 
dynamically varying metabolic activity and the constantly chang- 
ing size of its individual molecules. The studies indicate that 
individual glucose units or residues are being added to or 
separated from parent glycogen molecules in an almost never- 
ending process, some molecules growing while others are shrink- 
ing, so that the glycogen molecule in the living animal is never 



- Ik - 

finished. Glucose molecules can be readily deposited when avail- 
able or quickly mobilized for energy production when needed. 

Work is continuing on a variety of 5-carbon sugars, the 
pentoses, because of the demonstration that they participate as 
actively in biochemical processes as do the more familiar 6-carbon 
sugars, the hexoses. 

Fat Metabolism in Experimental Diabetes . In other intra- 
mural studies the close association of disturbances in fat metab- 
olism with alterations in carbohydrate metabolism have been demon- 
strated in an experimental study of rats made diabetic by total 
removal of the pancreas. Development of diabetic keto-acidosis 
occurred, simultaneously with blood sugar elevation, within two 
hours after the pancreas was removed. Administration of insulin 
corrected these indications of altered fat metabolism at a rate 
similar to the reduction in blood sugar, yet other observations 
showed that the fat disturbance is not due entirely to insulin 
lack. This study is being extended to inquire into the influence 
on ketosis of a variety of factors known to have various effects 
on diabetes, such as administration of fats, starvation, pregnancy, 
and the growth hormone of the pituitary. 

Blood Level of Circulating Insu li n . Arduous effort over 
several years has gone into the development of a sensitive and 
reliable assay of the circulating blood levels of insulin. With 
adequate sensitivity such an assay would be extremely valuable 
for a wide variety of studies of influences on insulin production 



- 15 - 

or inhibition. With the view of stimulation of effort and exchange 
of ideas on this difficult problem, the Institute in May 1957; 
assembled at Bethesda an international conference of the 50 most 
active diabetes investigators in the world, including a number of 
grantees. The conference revealed that extensive advances had been 
made in the development of insulin assay techniques, including a new, 
more specific immunologic method which promises to provide a means 
of measuring true insulin concentration in the blood, in contrast 
to other methods which indicate the aggregate action of insulin 
and other hormonal factors influencing glucose utilization. 

Action of Insulin . Substantial support for the idea that a 
principal site, if not the most important site, of insulin action 
lies in the transport of sugars across cell membranes in muscle has 
been provided by work supported by an Institute research grant. 
The mechanism of transport is not simple diffusion, but appears 
to involve combination of the sugar with a molecular constituent 
of the cell membrane. It was shown that not only glucose and 
galactose but other important sugars moved rapidly into muscle 
cells under the influence of insulin. As a result of this work 
it is now possible to say that there is no qualitative difference 
in the insulin response of heart, diaphragm, and skeletal muscle. 



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- 16 - 

RHEUMATIC DISEASES 

The rheumatic diseases constitute a large family of related 
disorders which are characterized by pain and stiffness in joints 
and muscles , often resulting in swelling and inflammation in af- 
fected areas. For the most part they are not fatal, although one 
group, the collagen diseases, often are. The test known and most 
vicious of these disorders is rheumatoid arthritis, which is 
responsible for much of the disability and crippling resulting 
from rheumatic disease. Other members of this disease family in- 
clude osteoarthritis, gout, rheumatic fever, non-articular rheuma- 
tism (fibrositis, neuritis, bursitis), and the collagen diseases, 
such as scleroderma, lupus erythematosus, and periarteritis nodosa. 
These diseases afflict approximately 10 million people in the United 
States and are a major cause of disability and crippling. 

Advances on many fronts of the research attack on the 
rheumatic diseases have been recorded during the past year which 
augur well for those who suffer the ravages of these painful and 
crippling disorders. Chemists, physiologists, pathologists, 
epidemiologists, biochemists, physicists, and even mathematicians, 
are joined in a concerted effort to win this battle in the shortest 
possible time,; Noted below are a few examples of the many forward 
steps accomplished. 



- 17 - 

New Diagnostic Test . A new, comparatively simple and ac- 
curate serological test for rheumatoid arthritis has "been developed 
by National Institute of Arthritis and Metabolic Diseases scientists, 
working in collaboration with colleagues in the National Institute 
of Allergy and Infectious Diseases. This test, known as the 
Bentonite Flocculation Test (BFT), has a number of advantages 
over older tests. 

Because of its comparative simplicity, the BFT may become 
the first of such diagnostic tests to be widely used by physicians. 
The speed with which it produces results is also an important 
factor in making it more practical to use, for an answer is avail- 
able in minutes rather than in hours or days. 

In related work, an attempt is being made to isolate and 
characterize the substance known as the "rheumatoid factor," which 
is found in the blood of persons with rheumatoid arthritis and 
which is the activating factor in all serological tests for the 
disease. Seeking this objective, an Institute scientist has de- 
veloped a precise quantitative method for measuring the activity 
of the factor which has a margin for error of only 5 percent, 
whereas previous methods varied in error from 100 to 200 percent. 

New Drugs Evaluated . In previous years, results with two 
potent antirheumatic agents have been reported- -prednisone and 
prednisolone. Along with a continued long-term study of these 
compounds, a number of active new drugs have been evaluated in 



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the past year. These studies have been carried out both by In- 
stitute grantees and by investigators at Bethesda, Among the new 
drugs tested were triamcinolone (a modification of prednisone) 
and several other new steroids; an antimalarial compound called 
chloroquine; and two derivatives of another type of antirheumatic 
drug, phenylbutazone. It has been found that while prednisone 
and prednisolone are effective antirheumatics, in some cases 
serious side effects are a hazard in long-term use. Triamcino- 
lone was found to have approximately the same antirheumatic 
potency as prednisone and, apparently, few advantages; the other 
steroid compounds tested had the same limitations as prednisone 
without some of the advantages One of the phenylbutazone de- 
rivatives on limited trial has provided moderate objective and 
subjective improvements in patients while the other produced no 
effect. Results obtained with chloroquine are not at this time 
of such nature as to permit final evaluation, 

More Learned About Gout . Overproduction of uric acid has 
now been clearly and consistently demonstrated to be the effective 
metabolic defect of primary gout in work started at Bethesda and 
extended both at the Institute and in grantee institutions. 

Detection by an Institute grantee of a purine metabolite 
in the urine which increases in amount during attacks of gouty 
arthritis constitutes the first indication of a specific link 
between the clinical and metabolic features of this disorder. 



- 19 - 

Colchicine administered orally has for many hundreds of 
years been used in the treatment of gout and is still perhaps the 
most effective agent in common use, hut most persons were found 
to be susceptible to extremely distressing gastrointestinal ef- 
fects brought on by it. These effects limited its usefulness. 
A systematic evaluation of intravenously administered colchicine 
recently conducted at the Institute has revealed that no lasting 
or serious side effects were encountered, and that the intravenous 
injection of the drug produced relief of the acute gouty attack 
more promptly and with fewer gastrointestinal symptoms than orally 
administered colchicine. 

Susceptibility to Osteoarthritis Investigated . Very little 
is known about the cause, predisposing factors, or even the course 
of osteoarthritis, but a detailed study of a group of intermarried 
families having a high prevalence of osteoarthritis, still incom- 
plete, has contributed information which confirms findings in 
animal studies to the effect that (l) susceptibility to osteo- 
arthritis is genetically transmitted, and (2) in those with in- 
herited susceptibility, obesity contributes significantly to the 
occurrence of the disorder. 

Genetic Trait Noted in Rheumatoid Arthritis . Evidence in- 
dicating that there is a genetic or familial trait in rheumatoid 
arthritis has been accumulating recently. Reports from this 
country and abroad indicate that on the basis of reactions to the 



- 20 - 

sheep cell agglutination test for rheumatoid arthritis ■, members 
of the families of arthritics, even though they have no symptoms 
of the disease themselves, reflect a higher rate of positive re- 
actions than do normal controls, 

METABOLISM: MOLECULAR DISEASES 
Major medical advances in the diagnosis and treatment of 
disease have in the past come relatively slowly and have in many 
instances stemmed from empiricists who depended largely upon ob- 
servation and experience rather than upon scientific experience. 
We are now veil into a period which is exemplified "by the 
recognition that an understanding of the basic chemical and bio- 
chemical reactions which occur in the cells of the body in health 
and disease is an absolute necessity before we can hope to solve 
the difficult problems of successful treatment and prevention of 
the chronic metabolic diseases. This period is further exemplified 
by the exploration of synthetic compounds whose design is based 
upon secure chemical, pharmacological, and physiological informa- 
tion, and by the use of such compounds in the treatment of disease,, 
The talents of the biochemist, synthetic chemist, the physiologist, 
the microbiologist, and the pharmacologist are being and must con- 
tinue to be applied with increasing intensity to the problems of 
the physician. Additionally, it must be recognized, a new era has 
begun in which the techniques and the talents modernly developed 
in the fields of physics and mathematics are to be applied to 
medical research problems. 



- 21 - 

An entirely new concept of "molecular diseases" has arisen 
in the past few years , resulting from important advances in "bio- 
chemical knowledge and techniques. Certain hereditary metabolic 
disorders have now been characterized as due to the partial or 
total lack of a specific enzyme necessary for catalysis of a vital 
metabolic process. In the absence or ineffective action of this 
process, death in infancy or early serious disease results. The 
term "molecular" arises from the fact that enzymes, missing or 
deficient in those diseases, have definite reproducible protein 
molecular structure. As with all proteins, the production of 
these enzymes is under genetic control, hence the hereditary 
nature of these disorders. It is not inconceivable that as 
science digs deeper and deeper into the metabolic processes of 
various diseases, more and more of them will be disclosed to be 
"molecular" in origin. 

Our findings concerning one of these diseases, galactosemia, 
were described two years ago. Since then, important additional 
information has been obtained regarding this milk sugar disorder 
and two more diseases, alcaptonuria and congenital non-hemolytic 
jaundice, can be added to the list. 

Galactosemia , In 1955/ Institute scientists reported dis- 
covery of the cause of, and development of a safe and relatively 
simple diagnostic test for a molecular disease known as galacto- 
semia, in which the absence of a single enzyme made it impossible 



- 22 - 

for the afflicted infant to properly digest one of the sugars in 
milk, bringing about a toxic condition which could lead, if not 
promptly diagnosed, to serious complications involving jaundice, 
mental retardation, and early death. 

Further work has unearthed an explanation for the fact that 
patients with galactosemia, while still lacking the essential 
enzyme, show an increased ability to tolerate milk as they advance 
in age„ A second enzymatic pathway for the breakdown of milk sugar 
has been found. The enzyme involved is very feeble in early life 
but later increases in activity, which explains the clinical ob- 
servation that patients can tolerate milk better as they grow 
older. 

Alcaptcnuria . Great potential significance is attached to 
the recent finding by Institute scientists of the cause of 
alcaptonuria, a rare disease often accompanied by a form of 
arthritis. Although persons with this disease are born with the 
basic defect in their metabolism, the disorder, during the first 
two decades of life is distinguished only by the presence in urine 
and perspiration of a substance which turns brown or brownish black 
upon exposure to air. This disease, it has now been shown, is 
caused by the absence or ineffectiveness of a single enzyme which 
is called homogentisic acid oxidase, 



- 23 - 

In addition to the importance of the discovery of the cause 
of the basic disorder, significance is attached to the possibility 
that this finding may provide, through its demonstrated relation- 
ship, guidance in the search for the cause of other types of 
arthritis. 

Congenital Non-hemolytic Jaundice , During the past year, a 
third "molecular" disease has been characterized by the demonstra- 
tion of a deficiency in an enzyme needed for an important biochemi- 
cal process. By means of a well -planned combination of laboratory, 
animal, and clinical studies, intramural investigators have demon- 
strated that congenital non-hemolytic jaundice is due to the lack 
of a specific enzyme needed to convert a constituent of bile called 
bilirubin into the form in which it can be excretedo 

Nucleic Acid s. Within the past few decades, great strides 
have been made in the elucidation of the structure of a difficult 
and important group of biological compounds, the proteins. The 
importance of this advance is well recognized, particularly since 
proteins make up the whole or a part of such essential substances 
as hormones, enzymes, and antibodies, 

A more difficult and perhaps even more important field is 
represented by the nucleic acids. Here, we approach the secrets 
of the viruses, of heredity, and perhaps of life itself. In very 
recent years research workers throughout the world, including 
grantees and intramural investigators of the Institute, have made 
a significant beginning in determining the structure and mode of 
synthesis by the body of nucleic acids. 



- 2k - 

Last year was reported to you the first synthesis of nucleic 
acids by enzymes isolated from living cells. This work has since 
then been extended to other types of nucleic acid and to other 
enzyme systems. In addition, some understanding has been gained 
of the methods by which the body controls the synthesis of these 
compounds . 

Identification of Factor Protective Against Dietary Liver 
Necrosis . An extensive study of experimental liver necrosis in 
animals culminated this year in identification of the active com- 
ponent of Factor 3> the dietary substance which prevents a variety 
of fatal deficiency disorders in rats, mice, and chicks. The 
essential ingredient was found to be the element, selenium. This 
material and two other factors, the amino acid cystine and Vitamin 
E, each protect against the multiple deficiency disease, but 
selenium is much more effective than either cystine or Vitamine E. 
The studies indicate that selenium is an essential trace element, 
probably acting as a catalyst in an essential metabolic process 
necessary for viability of the liver and of other organs. 

Many additional examples of research advances might be 
cited. These few, however, are illustrative and others will be 
discussed under "Research Highlights." 

CONCLUSIONS 

There has been presented a very brief resume of the work of 
our Institute in its laboratories and clinical facilities and of the 
stimulation, through grants, of research studies and training programs 



- 25 - 

in the many medical and research institutions throughout the 
country. The interest and support which this committee has evi- 
denced in each succeeding year since its inception has enabled 
the National Institute of Arthritis and Metabolic Diseases to as- 
sume the leadership you have intended in the search for knowledge 
into the cause, prevention, and cure of some of the most baffling 
diseases of mankind. 

Since these efforts involve to a great extent the association 
of members of the scientific and medical profession in working to- 
gether for the common weal and because we appreciate so very 
strongly the necessity for mutual costimulation of the Government 
scientist and his colleague in the great teaching universities and 
nongovernmental research institutions of this country, this report 
will close with brief reference to the constant exchange of 
scientific and medical talent between our Institute and these uni- 
versities and hospitals. Of course the majority of our investiga- 
tors reach us from university and hospital sources. But our parti- 
cular pride is that these young men, after two or three years with 
us, are in constant demand for places of leadership and respon- 
sibility in the top-flight medical schools and universities in this 
country. Several of our men return each year to enrich the staffing 
of these great institutions. Rather than feeling a constant sense 
of loss we take increasing satisfaction in the two-way channel which 
has been established, and great pride that the value of our environ- 
ment and the quality of research conducted at the National Institutes 
of Health is recognized to the fullest extent by the scientific and 
teaching world* 



SjMMARV OF OPENING STATEMENT 

by 

Director, National Institute of Allergy and Infectious Diseases 

Public Health Service 

CCKMITTEE ON APPROPRIATIONS 

1959 EXTIMATE 

"Allergy and Infectious Disease Activities" 

Public Health Service 

The 1959 budget proposal for this appropriation is 
,17,497,000. 

The National Institute of Allergy and Infectious Diseases 
conducts and supports research on a number of diseases which 
collectively represent our major cause of morbidity and rank high 
as causes of disability and death. These include allergic condi- 
tions, such as hay fever and asthma $ infectious disoases, such as 
the common cold, influenza, Colorado tick fever, and tuberculosis j 
and parasitic diseases, such as malaria. 

The virus diseases, particularly the gamut of respiratory 
viral illnesses, represent a new frontier in infectious disease 
research. The Institute is conducting extensive studies in this 
area, including epidemiological surveys in special population 
groups. The pandemic of Asian strain influenza has provided unique 
investigative opportunities, as in assessing the value of vaccines 
and developing new diagnostic methods. Other viruses associated 
with mild or severe respiratory symptoms are being discovered 
and characterized. 



!Y 



- 2 - 

Arthropcd-borne viruses prevalent in the tropics, and 
sometimes epidemic in the United States, will be studied through 
a new exploratory laboratory in the Panama Canal Zone: the 
niddle America Research Unit. 

Also in the field of tropical medicine, expanding malaria 
research by the Institute takes into account ths heavy national 
investment in eradication of this parasitic disease. 

Continued emphasis is being placed upon allergy-immunology 
and viral diseases, and the Institute facility for work with germ- 
free animals is being expanded. A new graduate training program 
has been initiated, and grants have been made for the support of 
special training in fields of critical scientific manpower 
shortage — in allergy-immunology and in tropical medicine and 
parasitology. 



OPENING STATEMENT 
Director, National Institute of Allergy and Infectious Diseases 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"Salaries, expenses, and grants, Allergy and Infectious 

Disease Activities" 

Mr. Chairman and Members of the Committee: 

The bddget proposal that is before you requests an 
appropriation of $17, J +97>000 for the activities of the National 
Institute of Allergy and Infectious Diseases in fiscal year 1959» 
This compares with $17,292,000 in availability for these same 
activities in 1958, 

The 1959 estimate reflects shifts in program emphasis to meet 
new needs in research and to ta*e advantage of new opportunities 
for critical study. The importance of allergic diseases to 
health and the need for progress in understanding the underlying 
causes of these diseases are recognized in the reprogramming of 
activities January 1959* Another subject receiving emphasis is 
that of insect-borne viral infections, particularly those which 
occur in Middle America and threaten the health of American 
citizens. By program rearrangement, additional support will be 
made available to augment research on acute respiratory virus 
diseases, germ-free animals, and malaria chemotherapy. 



■O.Q 



- 2 - 

Respirat o ry Virus Di sea se s 

The National Institute of Allergy and Infectious Diseases 
has a well-established and recognized reputation for intramural 
research achievements in the field of respiratory illnesses, 
including influenza. Within the last several years, scientists 
in this Institute and grant-supported laboratories have recog- 
nized at least 70 previously unknown viruses, i-lany are associated 
with respiratory diseases ranging in significance from the group 
generally known as the "common cold" to more serious illnesses, 
such as pneumonia. 

As methods for cultivation of these viruses improve and 
precise knowledge of their relative clinical importance increases, 
preventive measures, including vaccination, will advance rapidly. 
It has become increasingly clear that the "common cold" may be 
caused by any of a number of these viral agents, depending on 
many factors such as the season of the year and the age (respira- 
tory disease experience) of the patient. It also seems likely 
that infection of man by most of these viruses may be manifested 
by a gamut of respiratory symptoms. In orphanages and children's 
homes, where respiratory epidemics of one sort or another flourish 
almost continually, it is possible to follow the epidemiologic 
patterns of outbreaks of respiratory disease and to search for the 
causes. 

Within the last few weeks, for instance, Institute virolo- 
gists have uncovered two entirely new families of respiratory 
disease viruses. A newly devised method of detecting such agents 



- 3 - 
in tissue culture led to these discoveries. The new viruses 
appeared in at least two different parts of the country this fall, 
causing respiratory disease in infants and children. A signifi- 
cant proportion of these children developed pneumonia. Labora- 
tory studies of the viruses show them to be distinct from known 
types of influenza and from other recently described viruses, such 
as the adenoviruses and ECHO viruses. 

The epidemic of influenza of uncertain characteristics and 
potentialities this year represented an opportunity for respira- 
tory disease research. Before the epidemic was well under way in 
this country, the Laboratory of Infectious Diseases of the 
National Institue of Allergy and Infectious Diseases had pub- 
lished reports of a novel, time-saving laboratory method of 
identifying the new strain of influenza virus and other viruses 
by means of hemadsorption in tissue cultures. Our scientists 
also demonstrated, by a live-virus challenge experience in human 
volunteers, that the new Asian influenza vaccines made avail- 
able in July 1957 produced definite though not complete pro- 
tection both against the likelihood of infection and its 
severity. This evidence was one of the considerations which 
led to the decision to increase the potency of commercial vaccines. 

Together with the Armed Forces Epidemiological Board, this 
Institute supported extramural investigations by laboratories and 
scientists competent in this field. Some 40 request for influenza 
research grants were received and reviewed, of which 13 grants for 
ii>187, 347 were approved for immediate payment. Subjects of 



- 4 - 

investigation included diagnostic 'technology,? olipical aspects, 

therapeutic management, basic studies of the new influenze virus, 
vaccine effectiveness under varying conditions of concentration 
and injection, complicating disease agents, etiology and virulence, 
epidemiology in community and institutional populations, and 
establishment in lower animals. These studies are still under way. 

Arbor Viruses 

Among other viral diseases receiving increased attention 
are those caused by the ARBOR viruses (arthropod-borne, including 
those transmitted by mosquitoes) . Disease agents of this type 
may cause several forms of encephalitis (central nervous system 
involvement with varying degrees of paralysis) in man and domestic 
animals. At times, mosquito -borne virus encephalitis has been 
epidemic in regions of the United States. 

To investigate these and similar diseases the Department 
of Health, Education and Welfare, the Department of the Army, 
and the Panama Canal Zone Government, on October l6, 1957> 
authorized a field research party in the Canal Zone for a period 
of three years. This is known as the Middle America Research 
Unit and will be jointly staffed by the National Institutes of 
Health and the Walter Reed Army Institute of Research. The 
laboratory, which begins operation in February, will also 
investigate some of the local diseases that have been partic- 
ular problems to the military. Construction and equipment 
installations of a temporary nature are now under way. It will 
supplement and in no way interfere with or overlap the 



''i.'.'k'- :. 



- 5 - 
investigations of the Gorgas Memorial Laboratory in Panama, which 
are presently concerned largely with studies on yellow fever, 
cutaneous leishmaniasis, and sand- flies. 

Other Virus Diseases 

Among other viruses "being investigated is the one causing 
Colorado tick fever. This disease, common throughout the Rocky 
Mountain area, is a hazard to vacationers and students visiting 
these regions during the summer months. The Rocky Mountain 
Laboratory at Hamilton, Montana, studies its distribution, its 
spread by ticks, and clinical characteristics. These researches 
are directed toward effective methods of control, and the develop- 
ment of a vaccine now seems probable. 

New information has been obtained concerning more familiar 
viruses. The mumps virus, for example, has been shown to persist 
in the body longer than previously thought. Another virus thought 
by Russian investigators to be a new type of poliovirus (Type h) 
has been shown by Institute scientists to belong to the Coxsackie 
Group A family, and to be a cause of meningeal infections. It is 
probably capable of causing polio-like paralysis in children. 

There have been rapid developments in virology relating to 
a number of mammalian tumors. The Director of the National Cancer 
Institute has outlined this area of research as it applies to 
Cancer. Our investigative role is fundamental, examining such 
problems as the persistence of viruses within the cell itself. 
The Institute and its grantees are studying the nature of viruses 
and the means by which they live in and destroy cells, 



- 6 - 

considerations involving fundamental research on biological 
enzymatic reactions at the primary level of life processes. 
Basic Research on Viruses and Cells 
An understanding is gradually emerging of the mechanisms 
by which viruses reproduce themselves within the cell and utilize 
the material of the cell. New and fundamental information was 
obtained from studies on nutritional requirements of human cells 
during the past year. This concerns the biosynthesis of "non- 
essential" amino acids and their subtle but probably essential 
role in the survival and growth of cells. These developments, 
considered in relation to the highly significant work that was 
done on the essential amino acids during the previous year, have 
many implications that apply directly to problems now being 
studied in tissue culture systems, including antibody production, 
sensitization, phagocytosis, virus propagation, and cancer cell 
replication. One of the effects of manipulating the nutrition 
of cells has been to demonstrate quantitative differences in two 
important enzymes in different lines of the same cell. Other 
studies of metabolism of cells infected with viruses have demon- 
strated differences occurring in the protein and nucleic acid 
metabolism between normal and infected cells. Infected cells 
also have been found to release phosphates in a regular manner 
which can be correlated with observable cytopathic changes and 
the release of virus as determined by virus titer. These investi- 
gations are being carried on both in Bethesda and Rocky Mountain 
Laboratory at Hamilton, Montana. 



- 7 - 
Malaria 

As a world center for tropical disease research—an area 
increasingly neglected by most facilities since the end of World 
War II--the Institute may take credit for maintaining a continuity 
of advance against these diseases. Reprogramming in recent years 
has placed increasing emphasis on tropical medicine, especially 
on malaria studies. 

Millions of U. S. dollars are being spent on world-wide 
malaria eradication through WHO, ICA, UNICEF, and other inter- 
national organizations. The approach to this project is generally 
the use of residual insecticides, which as been successful in 
ridding large areas of malaria. However, there are places where, 
for various reasons, this technique is not effective. Here mass 
malaria chemotherapy must be relied upon for preventing the 
infection of mosquitoes until all transmission of malaria ceases 
and the disease is thus eradicated. This appears to be entirely 
possible if cheap, effective, non-toxic antimalarial drugs are 
available, which do not cause parasite resistance and which can 
be administered economically to large numbers of people with 
minimum supervision. 

Malaricidal drugs have been greatly improved since World 
War II, but additional basic and applied research is needed to 
produce compounds possessing all of these specifications, and 
thus to obtain the maximum return from the American investment 
in global malaria eradication. Primary emphasis will be placed 



- 8 - 
upon new methods of microbial study which have been developed in 
recent years, particularly the use of tissue cultures. Other 
fundamental research will include studies of genetic variation 
in strains of malaria parasites with relation to their suscepti- 
bility to drugs; work on the pharmacodynamic features of the 
clinical management of patients by newly developed therapeutic 
agents; and investigation on the basic mechanisms of cell para- 
sitism. 

Tuberculosis 

Progress in tuberculosis research is not rapid, but slowly 
the important elements in curative and preventive measures for 
this disease are being defined. Other groups in the PHS are at- 
tacking these problems from several standpoints. This Institute's 
research efforts in tuberculosis have been devoted primarily to 
immunologic techniques and prevention. Scientists of the Institute 
and its grantees employing newer methods break up tubercle bacilli 
and select active fractions for evaluation of vaccine potentialities. 

Many physicians dealing with tuberculosis in this country 
do not advocate the use of BCG vaccine except in non-immune people 
exposed to great risk of infection. This is because nearly all of 
the active cases now developing in the United States represent 
recrudescence of earlier mild or subclinical infection. Persons 
with naturally acquired subclinical infection have positive tuberc- 
ulin tests and are not candidates for BCG vaccine. Another 
deterrent to the use of BCG is the lack of uniformity of the pro- 
duct, except when made under skillful supervision. 



- 9 - 

The Surgeon General's Special Committee on Tuberculosis, 
the membership of which includes the most experienced tuberculosis 
clinicians and investigators in the United States, recently (June, 
1957) prepared a comprehensive report on this subject. The Commit- 
tee agreed that BCG did confer some protection against tubercu- 
losis, but questioned whether this was enough to justify its 
greater use in this country in light of the general progress in 
tuberculosis control and in the face of the several disadvantages 
noted. It believed that decisions as to its use in communities 
or population groups should be determined by the particular 
circumstances obtaining, and that in general it should be advo- 
cated for physicians, nurses, medical and nursing students, 
laboratory workers, hospital employees, persons unavoidably 
exposed to continued contact with infectious cases in the home, 
and for patients, inmates, and employees of institutions such 
as mental hospitals and prisons where case-finding programs 
indicate that exposure to tuberculosis is high. 

In view of these considerations, specialists in this area 
have devoted much time to the development of a more effective 
tuberculosis vaccine free from undesirable properties. This 
Institute has made ten grants in the amount of $2^0,000 supporting 
research relative to this subject. The grantees include the 
Nation's outstanding authorities on tuberculosis. Various fractions 
and extracts of tubercle bacilli and their parts, irradiated, pro- 
duced with Bpecial growth-promoting materials, and with other 



- 10 - 
special treatments, are being tried in different experimental 
systems. Related studies are being carried on in our own labora- 
tories. 

Allergy and Immunology 

Progress has been made in the professional staffing for 
this new program. One useful finding which has already appeared 
is the adaptation of the bentonite flocculation test for the 
diagnosis of rheumatoid arthritis . Collaborative clinical 
studies with investigators in the National Institute of Arthritis 
and Metabolic Diseases have shown it to be the most simple and 
specific diagnostic test available. Its application by clini- 
cians will expedite the early recognition of the disease. 

The scientists at Bethesda have concentrated on developing 
a basic laboratory to encourage original and novel approaches. 
On these projects just now getting under way with the leadership 
of Dr. Jules Freund, an internationally known investigator, will 
be built a clinical program directed toward solving problems in 
allergic diseases. 

The Institute has made 96 research grants ($1,381, 046) for 
basic and clinical studies of these important diseases which are 
being attacked from a great variety of standpoints. 

In an Institute grant-supported study at the University of 
Michigan, for example, a number of investigators have undertaken 
a study of atmospheric pollution by aeroallergens such as ragweed 
pollen. This comprehensive program of research includes inte- 
grated studies of the plant and its pollen, of the means by which 



-li- 
the pollen is dispersed in the atmosphere , and of the nature of the 
physiological reaction of sensitive individuals to it. Specialists 
in botany, internal medicine, meteorology, and public health are 
working cooperatively on the study. Several of the findings have 
already been published in scientific journals. They represent 
basic factual contributions on the effect of weather conditions 
on pollen dispersal and on various medical aspects of ragweed 
air pollution. For instance, subjective and objective asthma 
and hay fever symptoms were related to pollen counts, and at 
the same time respiratory evaluations and blood tests were done 
on patients to get a coordinated picutre of what is taking place. 
All of this information should provide a pattern for later at- 
tempts to find more effective means of relief for sufferers from 
hay fever and asthma. Ragweed pollen is being studied initially 
because it is one of the chief offenders among allergens in the 
United States. 

Several universities have begun grant -supported investiga- 
tions into the allergic contact dermatoses that are frequent 
causes of industrial absenteeism and a deterrent to productivity. 
Studies from different vantage points are under way at the Uni- 
versity of Pennsylvania, New York University-Bellevue Medical 
Center, the University of Cincinnati Medical College, and Washington 
University, St. Louis. Allergic contact dermatitis is frequently 
seen among workers who handle dyes and dye intermediates, rubber 
accelerators, photographic developers, antioxidants, soaps, insec- 
ticides, plastics, plants and plant derivatives, antibiotics, and 



- 12 - 

many of the new industrial materials now coming into use for the 
first time. People in every occupation, including the housewife, 
are often troubled by moderate or severe allergic reactions to 
materials with which they come in contact. 

Germ-Free Animal Studies 

The germ-free chamber for studying bacteriologically 
sterile animals offers a new dimension to the microbiologist, 
and has been described as a research tool comparable in poten- 
tial to the microscope. Well conceived and promising proposals 
for utilizing germ- free animals to answer fundamental questions 
about the precise role of bacteria in the production of disease 
await the availability of facilities for producing and maintain- 
ing these animals. 

The expansion of NIAID Section on Germ-Free Animal Studies 
continues, implementing directives of medical advisory groups and 
of the Congress, to give increased emphasis to this area of research 
in view of its special promise. The small group of specially trained 
scientists comprising the Germ-Free Section will shortly move to a 
new facility at NIH. Here, nine additional pressurized, stainless 
steel chambers have been installed and will be activated, in addition 
to the chamber now in use. Two of the new germ- free apparatuses will 
be maintained by NIAID for use by other Institutes. 

Similar pioneering studies by the LOBUND Laboratories at 
the University of Notre Dams, supported by research grants, have 



- 13 - 
maintained the continuity of this work and facilitated its 
organization in a number of other research centers in this 
country. 

Gorgas Memorial Laboratory 

This Laboratory, which is the operating research facility 
of the Gorgas Memorial Institute of Tropical and Preventive 
Medicine, Inc., was established in 1929 and is located in Panama 
City, Republic of Panama. It investigates diseases of the 
American tropics and is staffed by medical, entomologic, virologic, 
and parasitologic scientists. It has been a continuously pro- 
ductive source of new knowledge concerning malaria, helminthic 
infestations, insects of medical importance, tropical zoonoses, 
and a variety of microbiological infestations endemic to tropical 
America. Of late years, it has been supplying virologic informa- 
tion of great value to this country and to the Pan American 
Sanitary Bureau concerning the northward movement of yellow fever 
in monkeys and in man from Central into North America. Recent 
findings of the Laboratory indicate that yellow fever virus has 
been isolated from Guatemala near the Mexican border and has now 
been found in three species of Central American mosquitoes 
collected in Guatemala. One of these occurs also in the southern 
United States. 

Important observations have been made concerning the host 
reservoir and transmission of cutaneous leishmaniasis, a 



- Ik - 

disfiguring ulceration which occurs in Equatorial America. Organ- 
isms causing this disease have been isolated repeatedly from the 
forest -dwelling spiny rats, and lesions in man have been experi" 
mentally produced from such cultures. It is probable that the 
transmitting insect is a species of Phlebotomus sandfly which is 
capable of carrying this and certain other tropical infections 
elsewhere. 

The major portion of the operating funds of this Laboratory 
has been supplied by U. S. Congressional appropriation. The amount 
requested for fiscal 1959 is the same as the appropriation for 1958, 
$150,000, the maximum allowed by an act of Congress (H.R. 8128) 
passed in 1928. 

Graduate Training Grants 

A new program for this Institute, these grants authorized 
by Congress last year are being used to overcome some of the 
critical deficiencies in scientific manpower in allergy-immunology 
and tropical medicine and parasitology. 

Immunologic and allergic public health problems are of 
considerable magnitude, whereas there are very limited numbers 
of investigators competent in this area of research. Twelve 
of the first 30 grants for graduate training were awarded, 
therefore, for special training in immunology and allergy. 

There is also an inadequate supply of trained investigators 
in tropical medicine. After World War II, facilities for research 



- 15 - 
in this field were sharply reduced. The Institute is one of the 
few centers maintaining a continuity of effort against the tropical 
diseases. Eighteen of the first 30 grants were allotted for train- 
ing in tropical medicine and parasitology and related fields of 
mycology and rickettsiology. 

This program, a long-needed adjunct of the allergy and 
infectious diseases research activity, provides more adequate 
training in areas of critical scientific manpower shortage and 
removes a harrier to progress in the future. 

Budgetary Increases for 1959 

The only increases proposed are those necessary (l) to 
annualize the expanded research efforts in allergy and immunology 
($100,000) and in supporting the tropical viral studies planned 
in the Panama Canal Zone ($90,000), and (2) to augment the contri- 
bution of this Institute to the NIH Management Fund for centrally 
furnished research services ($30,000). 



SUMMARY OF OPENING STATEMENT 
by 

Director, National Institute of Neurological 
Diseases and Blindness 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

"Neurology and Blindness Activities, Public Health Service" 

The budget proposal for this appropriation in 1959 is 
$20,727,000. 

Important advances have been made during the past year in the 
program of research and training in the field of neurological and 
sensory disorders. Healthy growth has been demonstrated in the 
extramural program, not only in research grants but also in the 
training of research scientists and teachers at the post-graduate 
level. The trend, noted last year, toward the collaborative type 
of field investigations has continued to develop. The intramural 
program has been expanded and strengthened in both clinical and 
basic research on the central nervous system and its aberrations. 

Among the important developments in research during the past 
year are the following: regeneration and restoration of destroyed 
nervous tissue has been demonstrated in animals; methods of studying 
the ultraf ine structure of the central nervous system have been 
developed and utilized to provide new Information; early diagnosis 



- 2 - 
in blinding eye diseases has been developed further; certain 
inflammations of the eye have been found to be precursors of 
systemic disorders; diffuse damage of brain cells and behavioral 
evidence of brain damage resulting from neo-natal asphyxia has 
been demonstrated with animals. 

The cerebral palsy-mental retardation collaborative study 
of perinatal morbidity is well underway; electrophysiological and 
biochemical advances have been made in the understanding and con- 
trol of epileptic seizures; the technique of hypothermia has pro- 
vided improved surgical procedures for the repair of aneurysms of 
blood vessels in the brain with a marked reduction in operative 
mortality; surgical relief from involuntary movements in cerebral 
palsy and Parkinsonism has been improved; biochemical studies of 
myelin formation and degradation are providing new knowledge 
relative to multiple sclerosis; new types of muscle disorders have 
been identified and described; the study of the process of aging of 
the central nervous system accelerated; and investigations of possible 
organic factors in disorders of speech and hearing have been ini- 
tiated. 

The major increase in the extramural research grants program 
has occurred in the basic neurological sciences and in the collabor- 
ative investigations of perinatal factors related to neurological 
and sensory deficits of infancy and childhood. Significant in- 
creases occurred, also in the fields of hearing, the blinding 
diseases, cerebral vascular disorders, multiple sclerosis and 
musclar dystrophy. 



- 3 - 

Graduate training grants were increased in the fields of 
neurology, opthalmology, and otolaryngology, and new programs in 
the basic neurological sciences were initiated. Traineeships and 
fellowships were also increased. 

The Institute's plans for fiscal year 1959 are to continue 
to consolidate and implement the programs in research projects, 
"both basic and clinical, and the programs in collaborative and 
cooperative field investigations, within the level of the 1959 
budget allowances, It is intended as far as possible to maintain 
the current balance of effort between project research and field 
investigations. In the field investigations the Institute con- 
tinues to function as a central laboratory and to provide leader- 
ship, counsel and guidance, specifically in the areas of biometry 
and epidemiology. 



■V.i' 



OPENING STATEMENT 

*y 

Director, National Institute of Neurological 
Diseases and Blindness 

Public Health Service 

COMMITTEE ON APPROPRIATIONS 

1959 ESTIMATE 

for 

"Neurology and Blindness Activities, Public Health Service" 

Mr. Chairman, Members of the Committee : 

The budget proposal that is before you is for an appropriation 
of $20,727,000 for the activities of the National Institute of Neuro- 
logical Diseases and Blindness in fiscal year 1959« 

At the time of my appearance before this Committee last year, 
changes then developing in our program were outlined* It was stated 
that when our Institute was activated in fiscal year 1952, with 
only limited resources, the emphasis of the program was of necessi- 
ty centered on providing support for specific research projects to 
be undertaken by the then available and trained investigators,, 

The Institute early recognized, however, that the advance 
of research is largely dependent upon the availability of capable 
investigators. Therefore, a training program in neurology, with 
emphasis on both clinical and basic sciences, was initiated in 



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- 2 - 

fiscal year 1955* During the past two years, this program has been 
expanded to train investigators in the techniques of chemistry and 
physics, and to orient them to the advantages of utilizing these 
techniques in developing knowledge of the structure and function 
of nervous tissue. 

The growth of these far-reaching programs of research and 
training is shown by the progressive increase of funds made avail- 
able through appropriations from $1,250,000 in 1952 to $20,795,000 
in 1958* One sign of this growth is the rapid increase in member- 
ship of societies comprising scientists from the field of clinical 
neurology and also from the basic sciences of neuroanatomy, neuro- 
pathology, neurochemistry, and neurophysiology. 

The progressive broadening of the horizons of neurological 
research has now reached the stage where it is possible and profit- 
able to carry through research programs based upon concerted efforts 
of many individuals and institutions. This brings varied skills, 
techniques, and facilities to focus upon a single problem. This 
process is most clearly evident in the collaborative and cooperative 
field studies started last year and now well underway. It under- 
lies much of the progress to be reported today. 

These collaborative and cooperative studies represent a con- 
tinuing trend. However, they in no way detract from the support of 
capable individual investigators or individual institutions concerned 
with a specific project or with research into a specific disease 



- 3 - 
category. In short, the purpose of the collaborative approach is 
not to supplant the highly important work of the individual scien- 
tist but rather, to supplement his efforts in certain broad general 
areas. 

The National Institute of Neurological Diseases and Blindness 
continues to benefit from the expert counsel provided by the scien- 
tific leaders of research activities throughout the world. Through 
the National Committee for research in Neurological Disorders, 
professional societies and many voluntary health organizations 
provide information and guidance for the further development of 
the Institute's program in neurological and sensory disorders. 
Among the organizations represented on this Committee are : The 
American Academy of Neurology, United Cerebral Palsy, National 
Multiple Sclerosis Society, National Epilepsy League, Muscular 
Dystrophy Associations of America, the National Society for 
Crippled Children and Adults, National Association for Retarded 
Children, Association for the Aid of Crippled Children, and the 
National Foundation for Infantile Paralysis. 

GRANT PROGRAMS : RESEARCH AND TRAINING 

The extramural research and training programs of this Insti- 
tute have increased steadily with the increasing availability of 
trained scientists and teachers. The trend toward the team approach 
to complex medical problems has continued. 



- k - 

Research Projects 

During the fiscal year 1957; 6^0 grants totalling 
$9,296,122 were made. It i6 expected that 715 grants will be sup- 
ported by awards totaling $10,750,000 during fiscal year 195$« 

The recent increases in budget appropriations allowed a 
general expansion of the research effort on practically all aspects 
of neurological and sensory diseases as well as increased emphasis 
on fundamental studies. Although the amount of funds awarded for 
all facets of research increased, expansion in certain specific 
areas is worthy of mention. 

During the past year, research on general metabolic and de- 
ficiency disorders increased by almost 70 per cent. This expansion 
is believed to be due to the increased awareness of the value of the 
neurochemical and neuropharmacological approach to solving some of 
the most perplexing neurological problems. A like increase in 
research on injury to the nervous system from various causes other 
than trauma was registered. 

Research into the disorders of vision, which in previous 
years had remained fairly stable, increased by over 60 per cent. 
The major protion of this increase is attributable to renewed 
efforts to solve problems in retinopathy, uveitis, and keratitis. 

By far the greatest expansion, however, was registered in 
disorders of hearing and balance. To be sure, very little research 
in proportion to the importance of this subject was being done 



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- 5 - 
in this area previous to 1957. Nevertheless, an increase to 
$600,000 in 1957 > or over 300 per cent, is significant under any 
term of reference. It indicates a general awakening and realiz- 
ation of the gains to he made by research in the entire hearing and 
speech field. 

The collaborative and cooperative studies, particularly 
those of perinatal factors in cerebral palsy and mental retardation, 
and cerebral vascular disorders, have also expanded. These stud- 
ies, with other investigations, included ^1 grants totaling approxi- 
mately $2,250,000 in 1957 and comparable grants totaling $3,000,000 
will be made in 1958. 
Training 

The training grant program is producing more well trained 
research workers and teachers in the fields of neurological and 
sensory disorders. As a direct result, the basic science and 
clinical departments of the medical schools are being greatly 
strengthened and the research output is being increased. 

Evidence of the growth of the training programs is contained 
in the number and amounts of awards made during recent fiscal years. 
There were 109 such grants amounting to $2,825,089 in 1957* and 
there will be approximately 130 grants totaling $3,500,00 in 
fiscal year 1958. Similarly 75 traineephips were awarded in the 
amount of $500,152 in 1957; and approximately lUO trainees will be 
supported by awards totaling $1,000,000 in fiscal year 1958. 



- 6 - 

There were 285 fellowships amounting to $!+99,809 in 1957 » 
and with the allocation of $^ 51>000 it is estimated that 178 
fellowships will be awarded in 1958. ($77*000, which was origi- 
nally a part of this activity; will he used to support approxi- 
mately 17 post-sophomore and foreign fellowships under the 
National Institutes of Health appropriation. ) 

The training grant program in the field of hearing, which 
was begun in fiscal year 1957* now has 5 active grants amounting 
to $97,8^2, 

Training in the basic sciences related to neurological and 
sensory disorders has been established with 3 grants in the amount 
of $91,360. 

ADVANCES IN RESEARCH 

The major advances achieved by the National Institute of 
Neurological Diseases and Blindness in neurological and sensory 
research during 1957 are reviewed in the annual Highlights of 
Research Progress in Neurological and Sensory Disorders . Copies 
of this document are being submitted for the record. 

Some specific areas in which the more important research 
developments were attained include; advances in diagnostic techni- 
ques in disorders of vision; significant biochemical findings about 
multiple sclerosis; basic research findings concerning the regener- 
ation of nerve tissue. Still others are the development of new 



- 7 - 
brain surgery techniques; advances in the treatment of cerebral 
palsy and Parkinson's disease; and the development and use of a 
technique which is providing significant information about the 
fine structure and function of the central nervous system. 

Last year, another development in diagnostic techniques 
which contributes to the safety of neurosurgical procedures was 
reported. This was the method of local scanning for the detection 
of brain tumors, utilizing radioactive isotopes, which has been 
under investigation by Institute scientists during the last few 
years. This technique has been developed to a high degree of 
effectiveness and a standardized instrument is being prepared for 
general use. 

While these and other advances in specific areas of neuro- 
logical and sensory disorders are described in the Annual Highlights, 
the Institute has in operation certain comprehensive programs. Such 
programs are directed to a research attack by many kinds of scien- 
tists on specific diseases of complex origin. These programs and 
the disorders on which they concentrate merit consideration. 

CEREBRAL PALSY 

The most inclusive example of the same type of attack is 
the Institute's collaborative field investigation program, designed 
to uncover the causes of cerebral palsy, mental retardation, and 
other neurological and sensory disorders of infancy and childhood. 
Conceived in 195*+> this program, in which the Institute serves as 
a central laboratory, and as a coordination center for statistics 
on cases, was initiated last year. 



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- 8 - 

Since last year's report, 11 institutions have joined the 
program so that there are now 13 collaborating institutions, and 
over 150 physicians, scientists, and technologists all actively 
engaged in this program. During fiscal year 1958, several more 
will be added. 

Cerebral palsy and other neurological and sensory defects 
arising in early life, because of the large numbers of individuals 
involved and the serious and prolonged disability which they produce 
are major medical and social problems. It has been shown that a 
large proportion of cerebral palsied individuals are damaged by 
reason of some event or circumstance occurring during pregnancy 
or in the period of labor and delivery, A certain additional 
number of children develop cerebral palsy as a result of injury 
or illness occurring in infancy. Knowledge of those circumstances 
and events during pregnancy or at birth which lead to injury and 
maldevelopment of the child will lead to better means of prevention 
and treatment of these disorders. 

During fiscal year 1957 and the first half of fiscal year 
1958, emphasis has been primarily with the organization of the 
collaborating institutions, the employment of the essential person- 
nel, and the preparation of a scientific protocol or detailed o» 
du bmilrtL experimental design for the investigations. The program 
envisages the evaluation of the genetic, familial, and constitutional 



•SfSttr 



- 9 - 
background of the parents, their social and economic status, 
their education and general level of intelligence, the emotional 
and physical health of the mother, and the complications of preg- 
nancy, labor and delivery,, These observations will be correlated 
with the eventual health of the offspring, especially as it concerns 
cerebral palsy, mental retardation or other neurological and sensory 
disorders of early life. 

There are two unique features of this collaborative study. 
The first lies in the nature of the collaboration. It requires an 
extremely close cooperation among the several institutions involved. 
Equally important, however, is the fact that this is a study in- 
volving many kinds of specialists. Within each institution, there 
are 10 to 15 different areas of scientific interest represented. 
The program is providing a powerful influence for cutting across 
scientific boundaries and for encouraging an exchange of techniques 
and information on many scientific levels, 

The impact of this collaborative study already has extended 
far beyond the study itself through its effect on members of the 
obstetrical, pediatric, and neurological disciplines. They are 
becoming increasingly aware of the importance of this phase of 
medicine. This awareness is reflected in part by the greater 
number of applications for special traineeships in pediatric 
neurology. The collaborative study is thus providing a valuable 
stimulus toward one of the important objectives of this Institute-- 
that of focusing attention on the importance of neurological disorders 
in infancy and childhood, a long neglected field. 



- 10 - 

MENTAL RETARDATION 

The importance of the collaborative study for cerebral 
palsy is equalled by its importance in the field of mental retard- 
ation. Here again,, it is an established fact that the majority 
of severely retarded individuals owe their retardation to factors 
existing at or prior to the time of birth. The nature of these 
factors is only dimly understood at the present time. The coll- 
aborative study is the first step toward spotlighting those factors 
which are relevant and subjecting those under suspicion to intense 
investigation. 

The problem of mental retardation, however, is one which 
extends far more widely throughout the field of medicine, for 
environmental prenatal factors are not the only ones which cause 
this disorder, It is known that a certain number of retarded in- 
dividuals owe their retardation to defects of body growth or 
metabolism. The discovery of methods for the prevention and 
treatment of the disabilities which result from metabolic derange- 
ments as phenylketonuria, has altered our feeling of helplessness 
about these conditions. It encourages the intense investigation of 
the retarded child in the search for chemical irregularities which 
might be corrected,. Advances in this area will parallel very 
closely advances in our knowledge of the chemical and anatomical 
structure of the nervous system. 



- 11 - 

The study of conditioning techniques in animals and of 
the effects of localized brain lesions on the learning process 
are throwing new light on the problems of intellectual impair- 
ment in humans. Animal studies have demonstrated that localized 
lesions of certain areas of the cortex produce specific defects 
such as those ordinarily looked for in the brain-damaged child. 
Lesions in the sensory area of the brain produce impairment 
of sensory perception. Conditioning and lesions in the occipital 
region are associated with the disturbances in visual learning. 

Of particular interest, however, is the demonstration 
that certain previously unexplored central structures in the 
nervous system play an important regulatory function affecting 
the activity of the whole sense system. Lesions in these areas 
produce impairment of overall functioning, such as attention, 
alertness, and responsiveness to external stimuli. Previous 
pathological studies of the brains of retarded individuals 
have completely overlooked the possible significance of these 
important areas. The scarcity of careful anatomical study of 
large numbers of retarded individuals is almost unbelievable 
at this time The Institute is supporting one lar.ge study of 
this sort, and is encouraging training programs for neuro- 
pathologists to undertake the painstaking analyses involved. 



I ■«• 



- 12 - 

CEREBRAL PALSY IN MONKEYS 
Closely related to the collaborative studies of cerebral 
palsy, mental retardation, and other neurological and sensory 
defects is the animal research program. Under this program, it 
was reported previously that the Institute had procured a free- 
ranging colony of monkeys on an offshore island in Puerto Rico. 
Progress with this colony has been most encouraging. There are 
255 Macaca mulatta monkeys now living in this free-range colony, 
the population of which has been increased. A caged colony of 
70 females has been established also. Studies underway include 
evaluation of the effects of hormonal imbalance during gestation, 
and behavioral studies in the free -ranging monkeys as compared to 

1 

the caged animals. Further studies are on the effects of commonly 
occurring diseases on the offspring, and especially the demonstration 
of the clinical and pathological effects of oxygen deprivation or 
asphyxia in the newborn animal. 

It already has been demonstrated that asphyxia of the new- 
born monkey leads to diffuse damage of brain cells. The nature of 
this damage is such that in a surviving animal the healing process 
would leave no permanent evidence of the loss of tissue. In humans, 
this means that pathological study in later life would give no clue 
of the occurrence of brain damage and loss of tissue from neonatal 
asphyxia. 



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- 13 - 
THE ASIAN INFLUENZA PROJECT 

The organization and facilities developed in these 
collaborative field investigations also are proving of value in 
connection with a closely allied concern — that of determining the 
effects of the Asian flu virus on the fetus * Previous studies 
have indicated that the virus of German measles is capable of 
producing fetal injury and maldevelopment. The Asian flu epidemic 
has provided a unique opportunity to find out whether this virus 
also is capable of producing fetal injury. Because of certain 
characteristics of the current epidemic, this Institute recognized 
that if specimens of blood serum could be obtained from pregnant 
women during and after this epidemic, it would be possible to 
determine whether they actually had been infected by this virus. 
Followup study of the children of those who were or were not so 
affected would provide evidence as to whether such infection does 
lead to increase in pregnancy wastage, maldevelopment, and defect 
of the child. At the present time, it is anticipated that approxi- 
mately 10,000 patients will be studied whose pregnancy occurred 
during the period of the Asian flu epidemic. 

CEREBROVASCULAR DISEASE 

The inadequacy is recognized of present methods of diagnosis, 
treatment, and rehabilitation of patients with cerebrovascular dis- 
eases, such as stroke, which rank third among all diseases as a 



- Ik - 

killer, and first as an adult crippler. Therefore, the Institute 
initiated a large and comprehensive cooperative program of clinical 
study of aneurysms (abnormal ballooning of blood vessel walls 
caused by injury or congenital factors), and of acute hemorrhage 
under the brain covering (subarachnoid) when the aneurysm breaks. 

In addition to studies of the causal factors related to 
these disorders, an evaluation will be made of various surgical 
and nonsurgical treatments in terms of the mechanism of action 
and in terms of the clinical results over long periods of time. 
Twelve medical centers are participating in this program. 

Another program has been launched to determine the effective- 
ness of anticoagulant drugs in preventing cerebral strokes. This 
new program, which is scheduled to last for three years, was made 
possible by grants totaling about $58,000 to the six participating 
medical research centers. An estimated 1800 patients will parti- 
cipate in the study. This total is far beyond the number which 
would be available for such an investigation by any one of the 
participating institutions, except over a period of many years. 

There is considerable evidence that anticoagulants properly 
administered tend to prevent the "slow" or "little" strokes, or 
their recurrence. Besides, this study, which will follow a uniform 
scientific protocol adopted by all the participating centers, will 
set up the machinery necessary for the evaluation of any preventa- 
tives or treatment that might be devised for strokes in the future. 



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- 15 - 
INFECTIOUS DISEASES OF THE NERVOUS SYSTEM 

The development of a vaccine for infantile paralysis has 
resulted in a shift of interest to other infectious diseases of the 
nervous system, especially in: regard to their aftermath of the brain 
damage sustained from the infection. Consequently, the Institute :' 
is developing a cooperative project for the study of the after- 
effects of insect-home diseases affecting the brain. 

These disorders are related to the occasional aftereffects 
of the common infections of childhood, such as mumps and measles. 
This investigation is a step toward determining how frequently 
such conditions lead to minor neurological defects manifested by 
disturbed behavior and inferior mental capabilities, and to what 
extent they can be prevented and treated. 

FIELD INVESTIGATION OF "KURU" 

Recently there was discovered among the natives of New 
Guinea an illness spoken of as "kuru," which means "the shakes." 
It occurs in a limited geographical area (the total population 
involved is probably about 15,000), but within this group approxi- 
mately one percent of all the people are affected, and it is 
reported to be responsible for 50 percent of all deaths in certain 
areas. 

Although the total number of affected individuals is small, 
the disease is of interest because of its similarity to a number 
of other, more widespread degenerative diseases of the nervous 
system. 



.-.-. i:' a. 



- 16 - 

The Institute has "been playing an active supporting role in 
these investigations being carried out in new fields. Pathological 
material, including six brains and other specimens forwarded to 
Bethesda from the field, are being studied. 

Preliminary autopsy findings suggest that the disease has a 
toxic origin, which has led to a field investigation for factors of 
diet which may be responsible. These studies may provide clues for 
the investigation of other nerve disease conditions of a serious 
nature. 

BIOSTATISTICAL ANALYSES AND CONTROLS 

In order to provide coordination and support for its several 
collaborative field investigations, the Institute is expanding its 
biometrics "branch. This branch has the heavy responsibility of 
processing the data derived from these collaborative studies. In 
many instances, the raw data itself is being forwarded to them for 
coding and analysis. Their guidance in study design and statistical 
analysis is in increasing demand not only by the cooperating groups 
but also by other investigators who turn to them for consultation. 

The status of research in various categorical diseases in 
which this Institute has particular interest is reviewed in the 
following section. 

EPILEPSY 

Research in epilepsy demonstrates how divergent approaches 
may converge at a point. Clinical studies of epilepsy have con- 
centrated primarily on the classification of seizures and on the 



- 17 - 
testing of drugs. The discovery of new anticonvulsant drugs has 
come about as the result of the screening and testing of new chemical 
compounds, first on animals and then on man. 

Through these studies the number of anticonvulsant drugs 
has risen from bromides as the only effective drug, until eight 
or ten useful drugs now are available to the clinician. The con- 
trol of seizures likewise has risen to the point where nearly eighty 
percent of epileptics may be managed effectively by drugs now avail- 
able. 

However, this type of research has been carried through 
almost exclusively on a clinical or patient care basis, and without 
knowledge of the basic processes involved, A further advance comes 
from the study of the actual physiological mechanisms of a seizure., 
Electroencephalographic techniques have demonstrated the importance 
of electrical changes occurring in the brains of epileptics * 

More recently, microelectrode techniques have indicated 
intense over-activity in the affected brain cells „ Researchers 
are now concentrating on the minor electrical changes in membrances 
of nerve processes and nerve cell bodies which occur during seizures. 

In fiscal year 1955> we reported that one of our research 
teams in Bethesda had opened a new vista in epilepsy research, 
through the development of a neurochemical approach. After pre- 
liminary investigations on animals, it was discovered that the 
brain cells of epileptics were deficient in glutamic acid. Also 



- 18 - 
discovered was the fact that this deficiency could be overcome 
by the administration of glutamine or asparagine. When the glu- 
tamic acid deficiency was overcome in this way, seizures of many 
epileptic patients were controlled. 

This breakthrough indicated that eventually epileptic 
seizures could be controlled by a natural body chemical, which 
would have infinite advantages over the currently used antiseizure 
drugs, since the latter are basically sedatives or depressants of 
the entire nervous system, and therefore often cause drowsiness and 
other annoying side effects. 

The Institute, in collaboration with six medical centers, has 
conducted extensive clinical studies for the evaluation of asparagine 
in the control of all types of epilepsy. The results indicate that 
asparagine is effective in about ^0 percent of all cases. However, 
it is relatively high in cost; there are difficulties in its admini- 
stration because of its bulk; and occasional undersirable gastro- 
intestinal side reactions follow. Therefore, it is apparent that 
asparagine could not compete successfully with other less expen- 
sive antiseizure drugs, except in unusual cases. 

V/hy asparagine is effective in some cases and not in others 
seems to be because (l) asparagine metabolizes rapidly, and there- 
fore in some patients may be destroyed before an adequate concen- 
tration is reached in the brain cells; and (2) other unknown factors 



"j\T 



- 19 - 
in brain metabolism may play a role in causing epileptic seizures. 
These are problems which are now being explored. 

For example, Institute scientists are devising methods for 
determining more accurately the levels of glutamine and asparagine 
in the body fluids of man, so as to better estimate its absorption 
by the brain cells. 

In addition, they are testing the role played by another 
substance in brain metabolism, which also may influence epileptic 
seizures. This substance is called gamma-aminobutyric acid or GAB* 
It has been shown that this chemical GAB, newly discovered in the 
brain, is related to glutamic acid metabolism in the brain and to- 
gether with vitamin B6 acts as an inhibitor of nervous activity. In 
fact, it has been shown that the changes produced in the excitability 
of brain cells by the administration of dilantin, an anticonvulsant 
drug, correlate with alterations in the concentration of GAB in the 
brain cells. These new discoveries provide new leads for the con- . 
trol of epileptic seizures through natural body chemicals. 

Also during the past year, Institute investigators have con- 
tinued their studies on the surgical treatment of epileptic patients, 
whose seizures result from a localized area of brain damage, in the 
temporal lobes of the brain. These are the patients suffering from 
so-called psychomotor epilepsy. Already 117 of these patients having 
seizures which were uncontrolled by medication have been operated on 



■ . I ■ • , ! , ,- . 



- 20 - 

in Bethesda, Of these, 55 percent have had one or less seizures 
since operation. Thirty-three percent had three or less seizures 
following surgical treatment, while only 15 percent had as many 
attacks after surgery as before. This 15 percent concerned patients 
with extensive damage in both temporal lobes of the brain. 
MULTIPLE SCLEROSIS AND DEMYELINATING DISEASES 

The Institute is pressing its attack on a serious problem 
of multiple sclerosis and demyelinating disorders, along five 
major fronts; (l) the anatomical; (2) the chemical; (3) the experi- 
mental; (k) the etiological; and (5) the epidemiological. 

This five -pronged exploration aims to discover the structural 
and chemical basis for the formation and construction of myelin, a 
fatty substance that makes up the protective sheath which insulates 
the nerve fiber tracts of the brain and spinal cord, and which dis- 
integrates in multiple sclerosis. Additional aims are to induce 
demyelinating disorders in animals for experimental studies; to 
evaluate suspected causes of demyelination, that is, microbes, 
viruses, allergy, toxins, or metabolic factors; and to study the 
variations in the prevalence of multiple sclerosis in different 
geographical areas, in order to uncover new leads. 

Last year, we reported that an Institute grantee, using the 
electron microscope, discovered that the myelin sheath of peripheral 
nerves (as opposed to the nerve of the brain and spinal cord) develop- 
ed as a result of a spiraling of the membrances of certain satellite 






I i 



- 21 - 

cells around the nerve fiber--cells known as Schwann cells. Later 
this clue led to the demonstration, also with the electron micro- 
scope, that myelin in the central nervous system originates also 
from satellite cells. These are known as neuroglia, more speci- 
fically the oligodendrocytes. These discoveries were major "break- 
throughs on a structural side. 

This year there has "been a breakthrough in chemical studies. 
An Institute scientist has discovered and characterized the specific 
manner in which a substance called sphingosine is synthesized in 
the body and has succeeded in synthesizing this vital compound in 
the laboratory by biochemical means. Sphingosine is a fatty amino- 
alcohol compound which is an essential element in the lipids (cere- 
brosides, gangliosides, sphingomyelin) found in the myelin sheath. 

Sphingosine and the lipids, of which it is a part, tentJ to 
disappear during the process of memyeli nation, as for example in 
multiple sclerosis. On the contrary these lipids accumulate in 
excessive amounts in such disorders as Tay-Sachs disease. The 
synthesis of sphingosine and the knowledge of its related enzyme 
systems, therefore, provides another experimental key to unlock the 
mystery that surrounds the formation and structure of myelin. 

As reported last year, it is now possible to produce in 
animals a disorder, closely resembling multiple sclerosis, which 
is called "allergic encephalomyelitis." Because of the important 
implications of this discovery, the Institute this fall sponsored 
a symposium on experimental allergic encephalomyelitis which has led 
to greater activity and research in this field. 



- 22 - 

The Institute has continued its search for a possible micro- 
biological etiology in multiple sclerosis. This year in Bethesda, 
thirty veil-documented cases of multiple sclerosis of increased 
severity were studied. The spinal fluid of these patients was 
carefully examined for micro-organisms. 

In addition, specimens of blood and spinal fluid from these 
patients were sent to the laboratories of the National Institute of 
Allergy and Infectious Diseases, and of the University of Cincinnati 
to investigate the validity of the antibody response to the antigen 
of material obtained from the U*S.S.R. The results of these studies 
have not as yet been reported. 

The Institute continues its epidemiologic studies of multiple 
sclerosis and demyelinating diseases with the hope of eventually 
turning up new clues for the causes of these conditions. Multiple 
sclerosis is far more common in the northern part of the United 
States than in the South, and it is more prevalent in European 
countries than in certain Eastern countries. Its prevalence in 
Japan is now being investigated under an Institute project. 
MUSCULAR DYSTROPHY AND NEUROMUSCULAR DISORDERS 

Muscular dystrophy and neuromuscular disorders have been a 
major research target of the Institute's clinical investigators and 
scientists since the inception of the Clinical Center program. . 
Because of the complexity of these conditions and their relative 



Yi<'.:>\ li 






- 23 - 
neglect in medical research, the attack on muscular dystrophy, like 
the one on multiple sclerosis, has "been a many disciplined one. ^ 
The attack uses new research techniques in laboratory research, and 
in testing animal and human patients «, Each year we have reported 
new findings from this research effort which all are essential for 
the final piecing together of the missing links in the understanding 
of these perplexing disorders,, 

All these studies are continuing unabated and new ones have 
been introduced. An important chemical constituent of dystrophic 
muscle has been isolated from patients and from mice having a 
disease resembling human muscular dystrophy. Plans are under way 
to synthesize this chemical substance in living uterine muscle. 

Using the basic data recently published in the Institute- 
created Atlas of Muscle Pathology , Institute investigators have 
discovered a new disease of muscle. New interest is focusing on 
the disease problems of weak-muscled infants, and it has been demon- 
strated that muscle biopsies are important to accurate diagnosis of 
such infants. Among 22 infants examined, k distinct types of muscle 
disease and nerve disease distinguishable by muscle biopsy have been 
differentiated. 

The mechanism of nerve-muscle transmission also is being 
attacked both in its basic mechanisms through animal experimentation, 
and in patients suffering from myasthenia gravis. Efforts are being 
made to demonstrate the presence of inhibitor-paralyzing substances 
in the sera of patients with myasthenia gravis, as well as to study 
the action of drugs. 



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By using a tagged isotope, researchers are studying what 
happens in a single enormous nerve cell of the squid. As yet, no 
final answers have been found as to the chemical process involved. 
But the answer for normal function would provide the basis for 
solving vital unknowns in nerve-muscle disease. 

PARKINSON'S DISEASE 

Important advances in the surgical treatment of involuntary 
movements already mentioned have a practical bearing on Parkinson's 
disease, familiarly known as "shaking palsy". 

Although surgical intervention offers considerable hope, the 
present therapy for relief of the rigidity, tremors, and involuntary 
movements of Parkinson's disease and related conditions still rely 
heavily on the use of drugs, A number of drugs have been found to 
be moderately effective in the relief of tremor and spasm. 

In the past, techniques for the evaluation of these drugs have 
been very limited since there is difficulty in establishing this type 
of clinical picture in experimental animals. Last year, it was 
reported that Institute scientists had discovered that continued 
doses of resperine in monkeys not only produce a clinical picture 
resembling Parkinsonism, but also produce anatomical changes in 
those areas of the brain frequently affected in this disease. Work 
is continuing to determine whether animals prepared by this technique 
may prove useful as experimental tools for the evaluation of anti- 
Parkinsonism drugs. 



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- 25 - 

These surgical and medical techniques used in Parkinson's 
disease are palliative only. The collaborative study of the after- 
effects of insect-borne virus diseases is one effort to seek cause 
and prevention. It is well known that the 1918 epidemic of influenza 
was followed by Parkinsonism in a considerable number of instances. 

Sporadic cases of Parkinsonism, resembling those which 
followed this epidemic, are still being seen but the nature of the 
virus, if one is responsible, has not yet been determined. The 
study of insect-borne encephalitides is one step toward clarifi- 
cation of this confused situation, 

EYE RESEARCH 

Since August 1955> when one of the world's most eminent 
research opthalmologists, Dr. Ludwig von Sallmann, joined this 
Institute, both basic and clinical research on diseases of the eye 
have increased steadily, A nursing unit of 25 beds for clinical 
research in opthalmology is in full operation. 

The research is directed at the blinding diseases, for many 
of which the cause is unknown and the treatment is palliative 
rather than preventive,; Glaucoma, cataract, uveitis, retinopathy, 
and ocular tumors continue to be the major causes of blindness. 

You will recall that the program on retrolental fibroplasia, 
which was initiated in 195^j w as successful. Within two years of 
cooperative research, the cause was identified and all the pedia- 
tricians and hospitals in the United States were alerted as to the 
proper preventive measures. Since 1956 the frequency of the disease 
has diminished greatly. 



- 26 - 

Last year you were advised that progress had been made in 
developing diagnostic and treatment techniques for uveitis, a 
blinding disease caused by tuberculosis, syphilis, brucellosis, and 
toxoplasmosis. With the cooperation of the National Institute of 
Allergy and Infectious Diseases, the evaluation of these techniques 
is continuing. Disorders of function of the thyroid gland seem to 
be related to recurrent cases of uveitis, so hormonal studies of 
these patients have been initiated. 

The use of radioactive indicators and autoradiographic 
techniques was reported two years ago. These developments are being 
improved further for the detection and localization of tumor6 of 
the eye and the orbit. The incorporation of radiophosphorus and 
other radioactive isotopes by malignant tumor cells are being 
studied. 

Last year electroretinography was reported to be useful in 
the detection and differential diagnosis of congenital versus 
environmental factors in diseases of the retina. With the use of 
additional techniques and with the aid of visiting scientists, these 
studies have been extended further. 

New research is adding credence to last year's report on the 
suspected neural mechanisms controlling pressure within the eye. 
The nervous pathways are being traced from the eye to centers in 
the brain. In addition, studies are underway of the mechanisms of 
inflow and outflow of fluids of the eye by recording changes in 
internal eye pressure for periods of time and under the effects of 
various drugs. These may lead to modifications in the diagnosis and 
treatment of glaucoma in patients. 



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Biochemical analyses of the lens and morphological studies 
of its ultra-fine structure are providing new leads to the factors 
which produce cataracts. 

AGING AND THE NERVOUS SYSTEM 

A reduction in intellectual faculties with advancing years 
is a phenomenon which has come to be looked upon almost as an in- 
herent characteristic of living organisms. However, experience in 
our life-time has demonstrated that the life span itself is not a 
fixed entity. It is in fact extremely unlikely that the aging pro- 
cess is an inevitable one. 

An exact knowledge of the anatomical and the chemical changes 
in advancing years is the first step toward the discovery of how to 
modify changes to achieve longer years of intellectual and physical 
usefulness. 

In January of this year the Institute sponsored a conference 
on the aging process of the central nervous system. The results 
were encouraging. An actual loss of nerve cells during aging has 
not been proven to be the basis of the aging process. There are 
changes in the dendrites --the fine connections which are associated 
with interactivity of the nerves and nerve cells within the brain-- 
and in addition, in the structures which provide nourishment to the 
nerve cells, but the nerve cells themselves may be spared. 

At this conference it was pointed out that, for further 
studies of the aging process, colonies of young and old animals 
should be established so that investigators studying changes of a 



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- 28 - 
progressive nature can be assured of animals of known age and 
health for study. Institute -supported laboratories are now 
developing colonies of guinea pigs and rats for this purpose. 
These animals are being used for the demonstration of changes in 
chemistry and structure taking place throughout the lifetime of the 
animal. 

DISORDERS OF HEARING AND SPEECH 

The multi disciplinary approach to a single problem is strik- 
ingly demonstrated when one considers recent advances in the field 
of hearing and speech. Here combinations of the techniques of 
anatomy, physiology, and psychology have led to new advances. 
Using new staining techniques, the anatomists have demonstrated in 
the brain and ear the exact location of the important nerve endings. 

By means of delicate recording needles thrust into these 
structures, the physiologists and biophysi cists have traced the 
activity of these nerves, testing their response within the sensitive 
receptor cells of the ear, along the pathways by which they are con- 
ducted to the brain, and in the brain itself. Using the conditioned 
reflex techniques of the psychologist, animals have been trained to 
respond to various types of auditory stimuli. 

Using the physiological techniques described above, the 
electrical changes of the ear and brain which accompany these 
patterned responses have been correlated. Changes in these patterns 
which result from disease or injury are demonstrated in operated 
animals. 



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Finally, through clinical examination of patients whose brains 
have been harmed by injury, strokes, or tumor, exact knowledge of 
the anatomical and functional derangements which results can be 
established. 

During the past year, the old concept that in left-handed 
individuals the speech center lies in the right side of the brain 
has been revised. Important differences in the language function 
between right-handed and left-handed individuals have been demon- 
strated. It has been shown that the majority of people have their 
brain center for speech in the left side of the brain, regardless 
of their handness. However, in left-handed individuals, the 
dominance of the left hemisphere is less complete, and surgical 
removal of this area is less likely to lead to permanent loss of 
speech than in the right-handed person. 

Such discoveries have important implications in respect to 
the training of children suffering from handicaps in speech and 
reading, as well as in the reeducation of adults whose language 
has been harmed through disease. 

NEUROSURGICAL INNOVATIONS 

Hypothermia or "cooling" of the brain is one of the recent 
innovations in neurological surgery. Formerly, it was not possible 
to interrupt the circulation to the brain for more than a few 
seconds. Now, it has been demonstrated, that, when the body and 



O-. 



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- 30 - 
the central nervous system are cooled the circulation can be inter- 
rupted for periods of time up to k-5 minutes without the occurrence 
of permanent brain damage. This diminishes the risk of hemorrhage 
in long, intricate, brain operations. 

Hypothermia has been particularly valuable in connection 
with aneurysms (ballooning) occurring in the brain. This condition, 
associated with weakness of the walls of the major arteries with 
resultant rupture, formerly carried a 50 percent mortality rate. 

Surgical intervention was extremely hazardous, largely 
because of the impossibility of cutting off the circulation during 
the time when repair of the artery was being attempted. Operation 
on aneurysms now can be carried out in a bloodless field — the vessel 
can be tied off or resewed with comparative ease. Thus, a marked 
reduction in operative mortality has been accomplished. 

In order to evaluate further the safety and effectiveness of 
these surgical procedures in respect to aneurysms of various cere~- 
bral arteries, the Institute has undertaken its cooperative investi- 
gation of surgical techniques in cerebral aneurysms, hemorrhages, 
blood clots, and malformations of the cerebral blood vessels . 
Another aim of this study is to make possible the more accurate 
selection, from among patients suffering from strokes, of those 
most likely to benefit from surgical or non-surgical therapies. 



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- 31 - 
PLMS FOR FISCAL YEAR 1959 
The Institute's plans for fiscal year 1959 are to continue to 
consolidate and implement the programs in research projects, both 
basic and clinical, and the programs in collaborative and cooperative 
field investigations, within the level of the 1959 budget allowances. 
It is intended as far as possible to maintain the current balance 
of effort between project research and field investigations. In 
the field investigations the Institute continues to function as 
a central laboratory and to provide leadership, counsel and guidance 
specifically in the areas of biometry and epidemiology. 



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